Compositions and methods for storage stable ophthalmic drugs

ABSTRACT

The present invention is related to methods of stabilizing an ophthalmic drug by adding a surfactant and a viscosity enhancer to the ophthalmic drug to create a composition wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 centipoise or more at shear rate of 1 per second at 25 degrees Celsius, filling the composition into a container; and storing the container at a temperature from about 2 degrees Celsius to about 25 degrees Celsius. The present invention is further directed to a container prepared by the methods of the present invention.

BACKGROUND OF THE INVENTION

Several ophthalmic drugs must be diluted just prior to instillation orif pre-formulated have a limited shelf life or require cold storage.Current ophthalmic drugs that suffer from stability issues includeaceclidine, latanoprost, latanoprost-timolol, chloramphenicol, azasite,cyclopentolate, proteins, peptides, amino acids and their derivatives.

Aceclidine has been shown effective for the treatment of glaucoma.Current aceclidine formulations require lyophilization of the aceclidineand mixing with a diluent just prior to instillation. Aceclidine hasalso been demonstrated to treat presbyopia, an eye condition thateffects almost every person starting around 40 years of age. See U.S.Pat. Nos. 9,089,562; 9,314,427; 9,320,709; 9,833,441; 9,844,537;9,968,594; 10,052,313; 10,064,818; 10,307,408; 10,617,763 and10,959,990.

Latanoprost has also been shown to effectively treat glaucoma. Likeaceclidine, latanoprost requires cold storage due to a limited shelflife at room temperature.

The instability of these ophthalmic drugs including aceclidine andlatanoprost cause inconvenience, reduced efficacy and increased costsfor both the subjects in need of these treatments and the companies thatmanufacture, sell and package these drugs.

Thus, there is a need in the art for a method of stabilizing ophthalmicdrugs such that an increase in shelf life is achieved.

SUMMARY OF THE INVENTION

In certain other embodiments, the present invention is directed to amethod of stabilizing an ophthalmic drug comprising the following steps:

-   -   a) adding a surfactant and a viscosity enhancer to the        ophthalmic drug to create a composition wherein the composition        has a viscosity of about 25 centipoise or less at a shear rate        of 1/1000 per second at 25 degrees Celsius and a viscosity of        about 70 centipoise or more at shear rate of 1 per second at 25        degrees Celsius;    -   b) filling the composition from step a) into a container; and    -   c) storing the container at a temperature from about 2 degrees        Celsius to about 25 degrees Celsius, preferably from about 2 to        about 8 degrees Celsius and more preferably at about 5 degrees        Celsius.

In certain other embodiments, the ophthalmic drug is selected from thegroup consisting of aceclidine, latanoprost, latanoprost-timolol,chloramphenicol, azasite, cyclopentolate, proteins, peptides, aminoacids, salts thereof, derivatives thereof and combinations thereof.

In certain other embodiments, the container of the present inventioncomprises a closure and a vessel wherein a portion of the closure and aportion of the vessel are sealed with an anti-leaching material selectedfrom the group consisting of biaxially-oriented polyethyleneterephthalate, polytetrafluorethylene and aluminum foil, preferablybiaxially-oriented polyethylene terephthalate.

In certain other embodiments, the container of the present invention isdisposed in a second container that is formed with or lined with ananti-leaching material selected from the group consisting ofbiaxially-oriented polyethylene terephthalate, polytetrafluorethyleneand aluminum foil, preferably biaxially-oriented polyethyleneterephthalate.

In certain other embodiments, the present invention is directed to amethod of stabilizing a composition comprising aceclidine comprisingstoring the composition in a container having a headspace at atemperature from about 22 degrees Celsius to about 25 degrees Celsius,wherein the container comprises a closure and a vessel wherein a portionof the closure and a portion of the vessel are sealed with ananti-leaching material selected from the group consisting ofbiaxially-oriented polyethylene terephthalate, polytetrafluorethyleneand aluminum foil and/or the container is disposed in a second containerthat is formed with or lined with biaxially-oriented polyethyleneterephthalate, polytetrafluorethylene and aluminum foil.

In certain other embodiments, the second container comprises a secondclosure, wherein the second closure provides an airtight seal.

In certain other embodiments, the airtight seal is resealable.

In certain other embodiments, the ophthalmic drug is aceclidine is at aconcentration from about 0.25% to about 4.0% w/v aceclidine.

In certain other embodiments, the methods of the present inventionprovide at least 90% stability of the ophthalmic drug for at least 7months, at least 8 months, at least 12 months, at least 15 months, atleast 18 months, at least 20 months or at least 22 months or at least 24months.

In certain other embodiments, the compositions of the present inventionhave a viscosity of about 0.5 centipoise or less at a shear rate of1/1000 per second at 25 degrees Celsius and a viscosity of about 150centipoise or more, preferably 300 centipoise or more at shear rate of 1per second at 25 degrees Celsius.

In certain other embodiments, the compositions of the present inventionhas a viscosity from about 75 to about 1,000 centipoise at a shear rateof 0.

In certain other embodiments, the present invention is directed to amethod of stabilizing a composition comprising aceclidine,hydroxypropylmethyl cellulose, polysorbate 80, mannitol, sorbate and anantioxidant selected from the group consisting of sodium ascorbate,sodium bisulfate, soidum metabisulfite, n-acetyl cysteine or acombination thereof comprising storing the composition in a containerhaving a head space at a temperature from about 2 degrees Celsius toabout 8 degrees Celsius, wherein the composition is filled into thecontainer under an inert gas overlay, preferably nitrogen and the headspace is purged with an inert gas, preferably nitrogen.

In certain other embodiments, the aceclidine is at a concentration fromabout 0.25% to about 4.00% w/v, the hydroxypropylmethyl cellulose is ata concentration from about 0.75% to about 1.25% w/v, polysorbate 80 isat a concentration from about 2% to about 4% w/v, mannitol is at aconcentration from about 2% to about 4% w/v, sorbate is at aconcentration from about 0.10% to about 0.12% w/v and the antioxidant isat a concentration from about 0.10% to about 0.25% w/v.

In certain other embodiments the present invention is directed to acontainer comprising an ophthalmic drug prepared by the processcomprising the steps of:

-   -   a) providing a container;    -   b) filling the container with a composition comprising an        ophthalmic drug, a surfactant and a viscosity enhancer,        preferably under an inert gas overlay, preferably nitrogen,        wherein the composition has a viscosity of about 25 centipoise        or less at a shear rate of 1/1000 per second at 25 degrees        Celsius and a viscosity of about 70 centipoise or more at shear        rate of 1 per second at 25 degrees Celsius;    -   c) optionally, purging a head space created during the filling        step b) with an inert gas, preferably nitrogen;    -   d) capping the container; and    -   e) optionally, storing the container at a temperature from about        2 to about 25 degrees Celsius, preferably from about 2 to about        8 degrees Celsius and more preferably at about 5 degrees        Celsius.

In certain other embodiments, the present invention is directed to amethod of stabilizing a composition comprising aceclidine comprisingstoring the composition in a container having a head space at atemperature from about 2 degrees Celsius to about 8 degrees Celsius,preferably at about 5 degrees Celsius.

In certain other embodiments, the compositions of the present inventionare filled into the container under an inert gas overlay, preferablynitrogen, preferably the head space is purged with an inert gas overlay,preferably nitrogen.

In certain other embodiments the present invention is directed to acomposition comprising from about 0.25% to about 4.0% w/v aceclidine andone or more means of stabilizing the composition selected from the groupconsisting of filling the composition into a container under an inertgas overlay, preferably nitrogen and purging a head space created duringfilling with the inert gas overlay, preferably nitrogen, having a totalviscosity of the composition of at least 50 centipoise or more, adding apreservative to the composition selected from the group consisting ofsorbate, benzalkonim chloride, sodium ascorbate, sodium bisulfate,sodium metabisulfite, n-acetyl cysteine and a combination thereof,

wherein the composition is stored at a temperature from about 2 to about8 degrees Celsius and wherein w/v denotes weight by total volume of thecomposition.

In certain other embodiments, the present invention is directed to amethod of treating presbyopia comprising administering to a subject inneed thereof a composition of the present invention.

In certain other embodiments, the present invention is directed to amethod of treating a refractive error of the eye in a subject in needthereof comprising administering to a subject in need thereof apharmaceutically acceptable amount of a composition of the presentinvention wherein the refractive error of the eye is selected frompresbyopia, myopia, hyperopia, astigmatism or a combination thereof.

The present invention is further directed to a method of increasing thevisual depth of field (i.e. depth of focus) secondary to pupil miosis,comprising administering to a subject in need thereof a pharmaceuticallyeffective amount of an ophthalmological composition of the presentinvention.

The present invention is further directed to a method of reducing theside effects of ophthalmic aceclidine administration by modulating theagonist effect on the ciliary body of the eye such that ciliary spasm,ciliary induced brow ache, and/or ciliary induced headache aresubstantially reduced or eliminated.

The present invention is further directed to a method of allowingbinocular physiologic topical presbyopic correction.

The present invention is further directed to a method of eliminating theneed for monocular limitation due to distance blur, or reduced totreatment of mild hyperopes to counteract induced myopic blur, astypically associated with pilocarpine, or pilocarpine and alpha agonistcombinations.

The present invention is further directed to a method of improving nearvision by increasing accommodation without reduction in distance visionsharpness. This is achieved by simultaneously increasing incrementalaccommodation, modulated so that while sufficient to provide additivenear vision enhancement, it remains at a rate of induction and totaldegree of accommodation such that the associated myopic blur does notbreak through the ability of the simultaneously induced pupil miosispinhole effect to filter the refractive error and maintain distancesharpness.

The present invention is further directed to a method of increasing thevisual depth perception upon improving near vision unaided comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of an ophthalmological composition of the present invention inboth eyes (binocular vision), wherein such binocularity further enhancesnear vision beyond that of either eye separately.

The present invention is further directed to a method of improvingvision in a subject with ammetropia (vision abnormality), comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of a composition of the present invention.

The present invention is further directed to a method of improvingvision in a subject with ammetropia, comprising administering to asubject in need thereof a pharmaceutically effective amount of acomposition of the present invention, wherein ammetropia is selectedfrom the group consisting of nearsightedness, farsightedness, regularastigmatism, irregular astigmatism and high degrees of regularastigmatism.

The present invention is further directed at eliminating opticalaberrations induced by corneal irregularity, opacities, or very highdegrees of regular astigmatism that include regions adjacent orperipheral to the central 1.5 mm optical zone, and thereby inducingimproved visual acuity and quality of vision by filtering out theseaberrant optics in those suffering from irregular astigmatism or highdegrees of more regular astigmatism, such as occurs in conditions suchas keratoconus, photorefractive keratectomy induced corneal haze,diffuse lamellar keratitis (“DLK”) (post-lasik DLK), other iatrogeniccorneal induced irregularity such as cataract incision, glaucomafiltering blebs, implanted glaucoma valves, corneal inlays with orwithout removal, ectasia post corneal surgery (lasik), and secondary toinfection.

The present invention is further directed at improving acuity relativeto existing uncorrected refractive error. Upon this improved acuity,patients now requiring toric contact lenses for astigmatism with reducedcomfort and optics that may shift during each blink may in many casesrequire only non-toric soft contact lenses or no contact lenses.Further, those requiring gas permeable contact lenses may no longerrequire contact lenses or only require much more comfortable softcontact lenses. Patients with high degrees of astigmatism may nowrequire no correction or reduced astigmatic correction. Patients withsmall to moderate degrees of nearsightedness may require less correctionor no longer require correction. Patients with small to moderate degreesof hyperopia (farsightedness) may require no correction or reducedcorrection.

The present invention is directed to methods and ophthalmologicalcompositions for improving eye sight. In a preferred embodiment thepresent invention is directed to methods and ophthalmologicalcompositions for the treatment of presbyopia. In a more preferredembodiment the present invention is directed to ophthalmologicalcompositions comprising aceclidine.

The present invention is directed to methods of treating irregularastigmatism, keratoconic ectasia, and low myopia, or hyperopia, with orwithout astigmatism, comprising administering to a subject in needthereof an ophthalmological composition of the present invention.

The present invention is further directed to a method of stabilizingaceclidine comprising providing a first composition comprising about1.75% w/v aceclidine and about 2.5% w/v mannitol in a first chamber anda second composition comprising about 0.01% w/v tropicamide, about 4.0%w/v polysorbate 80, about 1.25% w/v hydroxypropylmethyl cellulose, about0.10% to 0.12% w/v sorbic acid, about 0.1% w/vethylenediaminetetraacetic acid dihydrate, about 0.02% w/v benzalkoniumchloride and optionally, about 0.1% w/v sodium citrate or citrate bufferin a second chamber, wherein upon mixing the first composition and thesecond composition the efficacy of aceclidine is maintained for at leastone month.

The present invention is further directed to a method of stabilizingaceclidine comprising storing a composition of the present invention atfrom 0 degrees Celsius to 8 degrees Celsius.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphical representation of the effects of pilocarpine andaceclidine with or without tropicamide and with or without a carrier onnear and distance vision in a patient over the age of 45.

FIG. 2 is a graphical representation of the effects of addition ofnon-ionic surfactants and viscosity agents on near vision acuity andduration of effect. Line-Hours denotes lines improved times duration ofeffect.

FIG. 3 is a graphical representation of the Efficacy Index for formulas#L33-#L94. Box color denotes a comfort level of good for white, fair forcross-hatched and poor for black.

FIG. 4 is a graphical representation of percent stability of aceclidinecold storage compositions at 5 and 25 degrees Celsius over 30 months.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compositions and methods ofstabilizing an ophthalmic drug by formulating the drug in a combinationof surfactants and viscosity agents that achieve a nonlinear viscosityfor the composition and storing the composition in a container.

Definitions

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

The term “stabilizing”, as used herein, refers to any process whichfacilitates and/or enables an active agent to remain in solution. Theterm “stabilizing”, as used herein, also refers to any means or processwhich inhibits and/or reduces the tendency of an active agent includinga muscarinic agonist, including aceclidine, to degrade.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 5% w/v” is to be understood as“4.5% to 5.5% w/v.” Therefore, amounts within 10% of the claimed valueare encompassed by the scope of the claims.

As used herein “% w/v” refers to the percent weight of the totalcomposition.

As used herein the term “subject” refers but is not limited to a personor other animal.

As used herein, the term “container” refers to a pharmaceuticallyacceptable container comprising a chamber suitable to house a liquiddrug product. Containers include, for example, vials, syringes,capsules, and ampoules.

As used herein “head space” refers to the area within the chamber of thecontainer between the composition and the cap when the cap is orientedaway from the pull of gravity.

As used herein, the term “cap” or “closure” refers to any articlecapable of preventing the composition from exiting the container.

The term muscarinic receptor agonist (“muscarinic agonist”) encompassesagonists that activate muscarinic acetylcholine receptors (“muscarinicreceptors”). Muscarinic receptors are divided into five subtypes namedM1-M5. Muscarinic agonists of the present invention include thosemuscarinic agonists that preferentially activate M1 and M3 receptorsover M2, M4 and M5 receptors (“M1/M3 agonists”). M1/M3 agonists includebut are not limited to aceclidine, xanomeline, talsaclidine,sabcomeline, cevimeline, alvameline, arecoline, milameline, SDZ-210-086,YM-796, RS-86, CDD-0102A(5-[3-ethyl-1,2,4-oxasdiazol-5-yl]-1,4,5,6-tetrahydropyrimidinehydrocholoride), N-arylurea-substituted 3-morpholine arecolines,VUO255-035 (N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole -4-sulfonamide), benzylquinolone carboxylic acid(BQCA), WAY-132983, AFB267B (NGX267), AC-42, AC-260584, chloropyrazinesincluding but not limited to L-687, 306, L-689-660, 77-LH-28-1,LY593039, and any quiniclidine ring with one or more carbonsubstitutions particularly that include an ester, sulfur, or 5 or 6carbon ring structure including with substituted nitrogen(s) and oroxygen(s), or any pharmaceutically acceptable salts, esters, analogues,prodrugs or derivatives thereof. A preferred M1/M3 agonist isaceclidine. In a preferred embodiment, muscarinic agonist of the presentinvention include those muscarinic agonist that preferentially activateM1 and M3 over M2, M4, and M5; and even more preferably activate M1 overM3. In a more preferred embodiment muscarinic agonist of the presentinvention include those muscarinic agonists that only activate M1.

The term “aceclidine” encompasses its salts, esters, analogues, prodrugsand derivatives including, but not limited to, aceclidine as a racemicmixture, aceclidine (+) enantiomer, aceclidine (−) enantiomer,aceclidine analogues, including, but not limited to, highly M1 selective1,2,5 thiadiazole substituted analogues like those disclosed in Ward. J.S. et al., 1,2,5-Thiadiazole analogues of aceclidine as potent mlmuscarinic agonists, J Med Chem, 1998, Jan. 29, 41(3), 379-392 andaceclidine prodrugs including but not limited to carbamate esters.

The term “selective α-2 adrenergic receptor agonists” or “α-2 agonist”encompasses all α-2 adrenergic receptor agonists which have a bindingaffinity of 900 fold or greater for α-2 over α-1 adrenergic receptors,or 300 fold or greater for α-2a or α-2b over α-1 adrenergic receptors.The term also encompasses pharmaceutically acceptable salts, esters,prodrugs, and other derivatives of selective α-2 adrenergic receptoragonists.

The term “inert gas” refers to gases that are chemically inert and donot react with other compounds. Inert gases include, but are not limitedto, helium, neon, argon, krypton, xenon, radon and nitrogen.

The term “low concentrations” or “low-dose” of alpha-2 adrenergicreceptor agonists refers to concentrations from between about 0.0001% toabout 0.065% w/v; more preferably, from about 0.001% to about 0.035%w/v; even more preferably, from about 0.01% to about 0.035% w/v; andeven more preferably, from about 0.03% to about 0.035% w/v.

The term “brimonidine” encompasses, without limitation, brimonidinesalts and other derivatives, and specifically includes, but is notlimited to, brimonidine tartrate,5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, and Alphagan®.

The terms “treating” and “treatment” refer to reversing, alleviating,inhibiting, or slowing the progress of the disease, disorder, orcondition to which such terms apply, or one or more symptoms of suchdisease, disorder, or condition.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable (i.e. without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner).

As used herein, the term “pharmaceutically effective amount” refers toan amount sufficient to effect a desired biological effect, such as abeneficial result, including, without limitation, prevention,diminution, amelioration or elimination of signs or symptoms of adisease or disorder. Thus, the total amount of each active component ofthe pharmaceutical composition or method is sufficient to show ameaningful subject benefit. Thus, a “pharmaceutically effective amount”will depend upon the context in which it is being administered. Apharmaceutically effective amount may be administered in one or moreprophylactic or therapeutic administrations.

The term “prodrugs” refers to compounds, including, but not limited to,monomers and dimers of the compounds of the invention, which havecleavable groups and become, under physiological conditions, compoundswhich are pharmaceutically active in vivo.

As used herein “salts” refers to those salts which retain the biologicaleffectiveness and properties of the parent compounds and which are notbiologically or otherwise harmful at the dosage administered. Salts ofthe compounds of the present inventions may be prepared from inorganicor organic acids or bases.

The term “higher order aberrations” refers to aberrations in the visualfield selected from starbursts, halos (spherical aberration), doublevision, multiple images, smeared vision, coma and trefoil.

The term “cold chain” refers to storage at temperatures from about 2 toabout 8° C. from manufacture to immediately prior to administration.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids or bases. The phrase “pharmaceutically acceptable salt” meansthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1 et seq.

The salts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable organic acid. Representative acidaddition salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,hyaluronic acid, malic acid, sulphuric acid and phosphoric acid and suchorganic acids as oxalic acid, malic acid, maleic acid, methanosulfonicacid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(P)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, a heteroaryl group or other suitablesubstituent.

Methods of the Invention

In certain embodiments, the present invention is directed to a method ofstabilizing an ophthalmic drug comprising the following steps:

-   -   a) adding a surfactant and a viscosity enhancer to the        ophthalmic drug to create a composition wherein the composition        has a viscosity of about 25 centipoise or less at a shear rate        of 1/1000 per second at 25 degrees Celsius and a viscosity of        about 70 centipoise or more, preferably of about 150 centipoise        or more and more preferably at about 300 centipoise or more at        at shear rate of 1 per second at 25 degrees Celsius;    -   b) filling the composition from step a) into a container; and    -   c) storing the container at a temperature from about 2 degrees        Celsius to about 25 degrees Celsius, preferably from about 2 to        about 8 degrees Celsius and more preferably at about 5 degrees        Celsius.

In certain other embodiments, the compositions of the present inventionare filled into the container under an inert gas overlay, preferablynitrogen, preferably the head space is purged with an inert gas overlay,preferably nitrogen.

In certain other embodiments, the ophthalmic drug is selected from thegroup consisting of aceclidine, latanoprost, latanoprost-timolol,chloramphenicol, azasite, cyclopentolate, proteins, peptides, aminoacids, salts thereof, derivatives thereof and combinations thereof.

In certain other embodiments, the container of the present inventioncomprises a closure and a vessel wherein a portion of the closure and aportion of the vessel are sealed with an anti-leaching material selectedfrom the group consisting of biaxially-oriented polyethyleneterephthalate, polytetrafluorethylene and aluminum foil, preferablybiaxially-oriented polyethylene terephthalate.

In certain other embodiments, the container of the present invention isdisposed in a second container that is formed with or lined with ananti-leaching material selected from the group consisting ofbiaxially-oriented polyethylene terephthalate, polytetrafluorethyleneand aluminum foil, preferably biaxially-oriented polyethyleneterephthalate.

In certain other embodiments, the present invention is directed to amethod of stabilizing a composition comprising aceclidine comprisingstoring the composition in a container having a headspace at atemperature from about 22 degrees Celsius to about 25 degrees Celsius,wherein the container comprises a closure and a vessel wherein a portionof the closure and a portion of the vessel are sealed with ananti-leaching material selected from the group consisting ofbiaxially-oriented polyethylene terephthalate, polytetrafluorethyleneand aluminum foil and/or the container is disposed in a second containerthat is formed with or lined with biaxially-oriented polyethyleneterephthalate, polytetrafluorethylene and aluminum foil.

In certain other embodiments, the second container comprises a secondclosure, wherein the second closure provides an airtight seal.

In certain other embodiments, the airtight seal is resealable.

In certain other embodiments, the ophthalmic drug is aceclidine is at aconcentration from about 0.25% to about 4.0% w/v aceclidine.

In certain other embodiments, the methods of the present inventionprovide at least 90% stability of the ophthalmic drug for at least 7months, at least 8 months, at least 12 months, at least 15 months, atleast 18 months, at least 20 months or at least 22 months or at least 24months.

In certain other embodiments, the compositions of the present inventionhave a viscosity of about 0.5 centipoise or less at a shear rate of1/1000 per second at 25 degrees Celsius and a viscosity of about 150centipoise or more, preferably 300 centipoise or more at shear rate of 1per second at 25 degrees Celsius.

In certain other embodiments, the compositions of the present inventionhas a viscosity from about 75 to about 1,000 centipoise at a shear rateof 0.

In certain other embodiments, the present invention is directed to amethod of stabilizing a composition comprising aceclidine,hydroxypropylmethyl cellulose, polysorbate 80, mannitol, sorbate and anantioxidant selected from the group consisting of sodium ascorbate,sodium bisulfate, soidum metabisulfite, n-acetyl cysteine or acombination thereof comprising storing the composition in a containerhaving a head space at a temperature from about 2 degrees Celsius toabout 8 degrees Celsius, wherein the composition is filled into thecontainer under an inert gas overlay, preferably nitrogen and the headspace is purged with an inert gas, preferably nitrogen.

In certain other embodiments, the aceclidine is at a concentration fromabout 0.25% to about 4.00% w/v, the hydroxypropylmethyl cellulose is ata concentration from about 0.75% to about 1.25% w/v, polysorbate 80 isat a concentration from about 2% to about 4% w/v, mannitol is at aconcentration from about 2% to about 4% w/v, sorbate is at aconcentration from about 0.10% to about 0.12% w/v and the antioxidant isat a concentration from about 0.10% to about 0.25% w/v.

In certain other embodiments the present invention is directed to acontainer comprising an ophthalmic drug prepared by the processcomprising the steps of:

-   -   a) providing a container;    -   b) filling the container with a composition comprising an        ophthalmic drug, a surfactant and a viscosity enhancer,        preferably under an inert gas overlay, prefereably nitrogen,        wherein the composition has a viscosity of about 25 centipoise        or less at a shear rate of 1/1000 per second at 25 degrees        Celsius and a viscosity of about 70 centipoise or more at shear        rate of 1 per second at 25 degrees Celsius;    -   c) optionally, purging a head space created during the filling        step b) with an inert gas, preferably nitrogen;    -   d) capping the container; and    -   e) optionally, storing the container at a temperature from about        2 to about 25 degrees Celsius, preferably from about 2 to about        8 degrees Celsius and more preferably at about 5 degrees        Celsius.

In certain other embodiments the present invention is directed to acomposition comprising from about 0.25% to about 4.0% w/v aceclidine andone or more means of stabilizing the composition selected from the groupconsisting of filling the composition into a container under an inertgas overlay, preferably nitrogen and purging a head space created duringfilling with the inert gas overlay, preferably nitrogen, having a totalviscosity of the composition of at least 50 centipoise or more, adding apreservative to the composition selected from the group consisting ofsorbate, benzalkonim chloride, sodium ascorbate, sodium bisulfate,sodium metabisulfite, n-acetyl cysteine and a combination thereof,

wherein the composition is stored at a temperature from about 2 to about8 degrees Celsius and wherein w/v denotes weight by total volume of thecomposition.

Compositions of the Invention

Ophthalmic drugs suitable for use in the present invention include, butare not limited to, aceclidine, latanoprost, latanoprost-timolol,chloramphenicol, azasite, cyclopentolate, proteins, peptides, aminoacids, salts thereof, derivatives thereof and combinations thereof.

Surfactants suitable for use in the present invention include nonionic,ionic and amphoteric (zwitterionic) surfactants. In a preferredembodiment, the surfactant used in the present invention are at aconcentration above the critical micellar concentration for thatsurfactant.

Nonionic surfactants suitable for the present invention includecyclodextrins, polyoxyl alkyls, poloxamers, polysorbates or combinationsthereof. Preferred embodiments include Poloxamer 108, Poloxamer 188,Poloxamer 407, Polysorbate 20, Polysorbate 80, ionically charged (e.g.anionic) beta-cyclodextrins with or without a butyrated salt (Captisol®)2-hydroxypropyl beta cyclodextrin (“HPβCD”), alpha cyclodextrins, gammacyclodextrins, Polyoxyl 35 castor oil, and Polyoxyl 40 hydrogenatedcastor oil or combinations thereof. Further, substitution of othernonionic surfactants compatible with ophthalmological use allows forsimilar formulation advantages, which may included but is not limited toone or more of a nonionizing surfactant such as poloxamer, poloxamer103, poloxamer 123, and poloxamer 124, poloxamer 407, poloxamer 188, andpoloxamer 338, any poloxamer analogue or derivative, polysorbate,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, anypolysorbate analogue or derivative, cyclodextrin,hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomlymethylated β-cyclodextrin, β-cyclodextrin sulfobutyl ether,γ-cyclodextrin sulfobutyl ether or glucosyl-β-cyclodextrin, anycyclodextrin analogue or derivative, polyoxyethylene, polyoxypropyleneglycol, an polysorbate analogue or derivative, polyoxyethylenehydrogenated castor oil 60, polyoxyethylene (200) , polyoxypropyleneglycol (70), polyoxyethylene hydrogenated castor oil, polyoxyethylenehydrogenated castor oil 60, polyoxyl, polyoxyl stearate, nonoxynol,octyphenol ethoxylates, nonyl phenol ethoxylates, capryols, lauroglycol,polyethylene glycol (“PEG”), Brij® 35, 78, 98, 700 (polyoxyethyleneglycol alkyl ethers), glyceryl laurate, lauryl glucoside, decylglucoside, or cetyl alcohol; or zwitterion surfactants such as palmitoylcarnitine, cocamide DEA, cocamide DEA derivatives cocamidopropylbetaine, or trimethyl glycine betaine, N-2(2-acetamido)-2-aminoethanesulfonic acid (ACES), N-2-acetamido iminodiacetic acid (ADA),N,N-bis(2-hydroxyethyl)-2-aminoethane sulfonic acid (BES),2-[Bis-(2-hydroxyethyl)-amino]-2-hydroxymethyl-propane-1,3-diol(Bis-Tris), 3-cyclohexylamino-l-propane sulfonic acid (CAPS),2-cyclohexylamino-1-ethane sulfonic acid (CHES),N,N-bis(2-hydroxyethyl)-3-amino-2-hydroxypropane sulfonic acid (DIPSO),4-(2-hydroxyethyl)-1-piperazine propane sulfonic acid (EPPS),N-2-hydroxyethylpiperazine-N′-2-ethane sulfonic acid (HEPES),2-(N-morpholino)-ethane sulfonic acid (MES), 4-(N-morpholino)-butanesulfonic acid (MOBS), 2-(N-morpholino)-propane sulfonic acid (MOPS),3-morpholino-2-hydroxypropanesulfonic acid (MOPSO),1,4-piperazine-bis-(ethane sulfonic acid) (PIPES),piperazine-N,N′-bis(2-hydroxypropane sulfonic acid) (POPSO),N-tris(hydroxymethyl)methyl-2-aminopropane sulfonic acid (TAPS),N-[tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropane sulfonic acid(TAPSO), N-tris(hydroxymethyl) methyl-2-aminoethane sulfonic acid (IES),2-Amino-2-hydroxymethyl-propane-,3-diol (Tris), tyloxapol, Solulan™ C-24(2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethanol)and Span® 20-80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, and sorbitan monooleate). In other embodiments theaddition of polysorbate 80 is preferred. In addition to the abovenonionic surfactants any nonionic surfactant is suitable for use in thepresent invention as long as the concentration of the nonionicsurfactant is such that it is above the critical micellar concentrationfor that non-ionic surfactant. Preferably, the nonionic surfactants usedin the present invention achieve submicron diameter micelles, morepreferably less than 200 nanometers and more preferably less than 150nanometers in diameter.

Ionic surfactants suitable for use in the pesent invention include, butare not limited to, anionic surfactants and cationic surfactants.Anionic surfactants suitable for use in the present invention include,but are not limited to, ammonium lauryl sulfate, dioctyl sodiumsulfosuccinate, sodium laureth sulfate, linear alkylbenzene sulfonate,sodium dodecyl sulfate, perfluorooctanesulfonate, sodium laurylsarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodiumstearte, lignosulfonate, sodium lauryl sulfate, α olefin sulfonate,ammonium laureth sulfate and sodium ester lauryl sulfate. Cationicsurfactants suitable for use in the present invention include, but arenot limited to benzalkonium chloride, benzethonium chloride,methylbenzethonium chloride, cetylpyridinium chloride, alkyl-dimethyldichlorobenzene ammonium chloride, dequalinium chloride, phenamyliniumchloride, cetyl trimethylammonium bromide, cetyl trimethylammoniumchloride, cetrimonium bromide and cethexonium bromide.

Amphoteric (zwitterionic) surfactants are any surfactant simultaneouslycarrying an anionic charge and a cationic charge. Amphoteric surfactantssuitable for use in the present invention include, but are not limitedto, alkyl or alkenyl-amphoacetates or ampho-diacetates,alkylampho-propionates or -dipropionates, alkyl amphohydroxypropylsultaines wherein the alkyl groups contain 8 to 24 carbon atoms such ascoco or lauryl.

Surfactants may be used in the present invention at a concentrationabove their critical micellar concentration. The critical micellarconcentration for any particular surfactant may be calculated by aperson of skill in the art. In a preferred embodiment, the concentrationof surfactants in the present invention is from about 1.5% to about 7%w/v. The selection of nonionic, cationic, or anionic surfactants isbased largely on 1) drug interaction; and 2) ability to permeate thecornea; where the surfactant quality combined with a viscosity agent iskey to the nonlinear (non-newtonian) viscosity created.

Ophthalmological in situ gels which may be substituted for or added inaddition to one or more surfactants include but are not limited togelatin, carbomers of various molecular weights including carbomer 934 Pand 974 P, xanthan gums, alginic acid (alginate), guar gums, locust beangum, chitosan, pectins and other gelling agents well known to experts inthe art.

In other preferred embodiments, the nonionic surfactant is polysorbate80 at a concentration from about 0.5% to about 10% w/v, more preferablyfrom about 1% to about 7% w/v and even more preferably from about 2% toabout 5% w/v, yet more preferably from about 2.5% to about 4% w/v andmost preferably at about 2.5% or 2.75% or 3% or 4% or 5% w/v.

Viscosity agents suitable for the present invention include, but are notlimited to gums such as guar gum, hydroxypropyl-guar (“hp-guar”), andxanthan gum, alginate, chitosan, gelrite, hyauluronic acid, dextran,Carbopol® (polyacrylic acid or carbomer) including Carbopol® 900 seriesincluding Carbopol® 940 (carbomer 940), Carbopol® 910 (carbomer 910) andCarbopol® 934 (carbomer 934), cellulose derivatives such ascarboxymethyl cellulose (“CMC”), methylcellulose, methyl cellulose 4000,hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyl propyl methyl cellulose 2906, carboxypropylmethylcellulose, hydroxypropylethyl cellulose, and hydroxyethyl cellulose,polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, gellan,carrageenan, alginic acid, carboxyvinyl polymer or combinations thereof.

Viscosity agents may be used in the present invention at a concentrationnecessary to achieve a viscosity of about 0.5 centipoise or less at ashear rate of 1/1000 per second at 25 degrees Celsius and a viscosity ofabout 150 centipoise or more, preferably 300 centipoise or more at shearrate of 1 per second at 25 degrees Celsius when combined with asurfactant above its critical micellar concentration.

In certain other embodiments, the compositions of the present inventionhas a viscosity from about 75 to about 1,000 centipoise at a shear rateof 0.

In another embodiment the viscosity agent will have an equilibrationviscosity less than 100 cps, preferably from about 15 to about 35 cps,and most preferably at about 30 cps. In a preferred embodiment theviscosity agent is Carbopol® 940 (carbomer 940) at a concentration fromabout 0.05% to about 1.5% w/v, preferably from about 0.09% to about 1.0%w/v, more preferably at 0.09%, 0.25%, 0.5%, 0.75%, 0.9% or 1.0% w/v. Incertain combinations it has been surprisingly discovered nonionicsurfactant/viscosity combinations may result in phase separation overtime with precipitate formation. In such situations, particularly forpolyoxyls, in a preferred embodiment polyoxyl 40 stearate, and cellulosederivatives, particularly hydroxypropylmethyl cellulose, use of anonpolysaccharide derivative for viscosity enhancement, such aspolyacrylic acid derivatives (carbomers, carbomer 934 or 940 inpreferred embodiments) may prevent such separation; or alternatively useof a non polyoxyl nonionic surfactant, such as polysorbate 80 witheither a cellulose derivative or noncellulose derivative viscosity agentmay be substituted.

In another preferred embodiment, the viscosity agent is carboxymethylcellulose at a concentration from about 1% to about 2% w/v, morepreferably from 1.35% to about 1.45% w/v and most preferably 1.42% w/vor 1.40% w/v.

In another preferred embodiment, the viscosity agent ishydroxypropylmethyl cellulose at a concentration from about 0.5% toabout 1.75%, and more preferably about 0.75% or 1.5%, still morepreferably from about 1.0% to about 1.5%, and most preferably at about1.25%.

Compositions of the present invention may further comprisecryoprotectants, polyols, bulking agents, solubilizers, antioxidants,tonicity adjustors, preservatives, Cryoprotectants are compounds thateither prevent freezing or prevent damage to compounds during freezing.As used herein, the term “cryoprotectant” or “cryoprotectants” includelyoprotectants. Cryoprotectants suitable for use in the subjectinvention include, but are not limited to, a polyol, a sugar, analcohol, a lower alkanol, a lipophilic solvent, a hydrophilic solvent, abulking agent, a solubilizer, a surfactant, an antioxidant, acyclodextrin, a maltodextrin, colloidal silicon dioxide, polyvinylalcohol, glycine, 2-methyl-2,4-pentanediol, cellobiose, gelatin,polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), formamide,antifreeze protein 752 or a combination thereof.

As used herein the term “polyol” refers to compounds with multiplehydroxyl functional groups available for organic reactions such asmonomeric polyols such as glycerin, pentaerythritol, ethylene glycol andsucrose. Further, polyols may refer to polymeric polyols includingglycerin, pentaerythritol, ethylene glycol and sucrose reacted withpropylene oxide or ethylene oxide. In a preferred embodiment, polyolsare selected from the group consisting of mannitol, glycerol,erythritol, lactitol, xylitol, sorbitol, isosorbide, ethylene glycol,propylene glycol, maltitol, threitol, arabitol and ribitol. In a morepreferred embodiment, the polyol is mannitol.

Sugars suitable for use in the present invention as cryoprotectantsinclude, but are not limited to, glucose, sucrose, trehalose, lactose,maltose, fructose and dextran.

In another preferred embodiment, alcohols include, but are not limitedto, methanol.

In one embodiment, the present invention individually excludes eachcryoprotectant from the definition of cryoprotectant.

Cryoprotectants may be at present in compositions of the presentinvention at a concentration from about 0.1% to about 99% w/v,preferably from about 1% to about 50% w/v, more preferably from about 1%to about 10% w/v.

As used herein “lower alkanols” include C1-C6 alkanols. Lower alkanols,suitable for use in the present invention include, but are not limitedto, amyl alcohol, butanol, sec-butanol, t-butyl alcohol, n-butylalcohol, ethanol, isobutanol, methanol. isopropanol and propanol.

Bulking agents suitable for use in the present invention include, butare not limited to, saccharide, polyvinylpyrrolidone, cyclodextrin andtrehalose.

Solubilizers suitable for use in the present invention include, but arenot limited to, cyclic amide, gentisic acid and cyclodextrins.

In a preferred embodiment, antioxidants suitable for use in the presentinvention include, but are not limited to, bisulfite, ascorbic acid,disodium- or tetrasodium ethylenediaminetetraacetic acid, citrate,butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), asulfoxylate, propyl gallate, an amino acid containing a thio group, anda thiol. In a preferred embodiment the antioxidant is disodiumethylenediaminetetraacetic acid at a concentration from about 0.005% toabout 0.50% w/v, citrate at a concentration from about 0.01% to about0.3% w/w, dicalcium diethylenetriamine pentaacetic acid (“Ca2DTPA”) at aconcentration from about 0.001% to about 0.2% w/v, preferably about0.01% w/v Ca2DTPA which can be formulated by adding 0.0084% w/v Ca(OH)2and 0.0032% w/v pentetic acid to the formulation and mixing slowly.Further combinations of antioxidants can be used. Other antioxidantsthat can be used with the present invention include those well known toexperts in the art such as ethylenediaminetetraacetic acid at aconcentration from about 0.0001% to about 0.015% w/v.

A tonicity adjustor can be, without limitation, a salt such as sodiumchloride (“NaCl”), potassium chloride, mannitol or glycerin, or anotherpharmaceutically or ophthalmologically acceptable tonicity adjustor. Incertain embodiments the tonicity adjustor is 0.037% w/v NaCl,

Preservatives that can be used with the present invention include, butare not limited to, benzalkonium chloride (“BAK”), sorbic acid,oxychloro complex, citric acid, chlorobutanol, thimerosal,phenylmercuric acetate, disodium ethylenediaminetetraacetic acid,phenylmercuric nitrate, perborate or benzyl alcohol. In a preferredembodiment the preservative is BAK, sorbic acid, oxychloro complex or acombination thereof. In a yet more preferred embodiment BAK is at aconcentration of about 0.001% to about 1.0% w/v, more preferably at aconcentration of about 0.007%, 0.01% or 0.02% w/v. In another preferredembodiment the preservative is perborate at a concentration of 0.01% toabout 1.0% w/v, more preferably at a concentration of about 0.02% w/v.

Various buffers and means for adjusting pH can be used to prepareophthalmological compositions of the invention. Such buffers include,but are not limited to, acetate buffers, citrate buffers, phosphatebuffers and borate buffers. It is understood that acids or bases can beused to adjust the pH of the composition as needed, preferably of 1 to10 mM concentration, and more preferably about 3 mM or 5 mM. In apreferred embodiment the pH is from about 4.0 to about 8.0, in a morepreferred embodiment the pH is from about 5.0 to about 7.0.

Aceclidine

One ophthalmic drug that may be stabilized by the methods of the presentinvention is aceclidine. Aceclidine is traditionally used as a treatmentfor glaucoma. When aceclidine is used to treat glaucoma it is normallystored in a two-bottle system; one bottle containing the lyophilizedaceclidine and the second bottle containing the diluent necessary toreconstitute the lyophilized aceclidine before topical instillation.Romano J.H., Double-blind cross-over comparison of aceclidine andpilocarpine in open-angle glaucoma, Brit J Ophthal, Aug 1970, 54(8),510-521. It is a further aspect of the present invention to provide anaqueous aceclidine composition that is stable in combination with coldchain storage. It is yet a further aspect of the present invention toprovide a method of stabilizing aqueous aceclidine by combiningeffective excipients, pH ranges and temperature ranges.

The compositions and methods of the present invention treat presbyopiaby improving depth of focus in patients with presbyopia by administeringan ophthalmological composition to the eye that reduces pupil dilationin the dark or in dim light, produces a particular degree and durationof miosis without accommodation, provides cosmetic whitening and/orinduce redness prophylaxis. The compositions and methods of the presentinvention also do not cause significant pupil rebound, tachyphylaxis,ciliary spasms, induction of myopia or reduction in distance vision.Additionally, the compositions and methods of the present inventionallow for the further improvement in visual acuity and depth perceptionof binocular (both eyes) treatment. The ophthalmological composition ofthe present invention surprisingly creates a pupil of from about 1.5 toabout 2.4 mm at the anterior iris plane and about 2.0 mm at the cornealsurface. Not wishing to be held to particular theory the clinical effectappears to involve both with modulated increase in accommodative toneand enhanced pinhole near depth of focus for improved near vision,estimated to be about −1.25 D or less, but restricted in power to remainwihin the range of pinhole correction for distance, found to be about−1.00 D or less creating a sum increase that may in some cases create anear vision add of +2.00 D or more without distance blur; and with areduction or ablation of the redness that is otherwise a hallmark of theuse of miotic agents. The pupil miosis of the present invention withsuch modulation and restriction of peak accommodative tone is superiorto the pinhole effect of the Kamra® and Flexivue Microlens® cornealinlays, allowing binocular treatment without peak dimming. Pupil miosisof the present invention with modulated accommodation is also superiorto inlays because the constriction of the actual pupil does not resultin the attendant severe night vision disturbance caused by the lightscattering borders of the pre-corneal pinholes created by the inlays.Further pupil miosis provides a greater field of vision and transmissionof more focused light, and in a discovered optimal pupil range of about1.5 mm to 2.1 mm using formulation discoveries of the present inventiondoes so with negligible to mild and very tolerable dimming and enhancedcontrast, distance vision, reduced glare at night, and improved nearvision.

The use of aceclidine has a minimal effect on the longitudinal ciliarymuscle, thus reducing risk of retinal detachment when compared to theuse of general muscarinic agonists such as pilocarpine and carbachol.The further inclusion of a cycloplegic agent resulted in only 0.04 mm ofanterior chamber shallowing. Aceclidine, particularly as enhanced forthe present invention, also has greater magnitude, duration, and controlof minimum pupil diameter than conventional pilocarpine with or withoutalpha agonists, and less anterior chamber inflammation with chronic use.Compositions of the present invention achieve these advantages byallowing both pinhole near vision depth perception benefit and modestaccommodative increase below the threshold of induced myopic distanceblur through the miotic pupil, whereby, not wishing to be held toparticular theory, it is believed the rate of miosis and the rate ofaccommodative increase maintain a synchronous balance in preferredembodiments allowing pinhole correction of otherwise inducedaccommodative blur in prior art applications of miotics for presbyopiccorrection. This combination thus is found to avoid the distance blurtypically seen in patients as a response to pilocarpine and/or carbacholinduced miosis without the formulation discoveries of the presentinvention, as well as the excessive accommodative myopia and ciliaryspasm manifested as brow ache or generalized migraine-like headache.

Such conventional formulations of pilocarpine, in order to effect anyreasonable duration of effect, are still restricted to less than orequal to about 4 hours in most cases, as the high ratio of accommodationto pupillary miosis requires minimal concentrations of pilocarpine ofabout 1.0% to minimize but not eliminate distance induced myopic blurand ciliary spasm. Further pilocarpine must be instilled monocularly tominimize intolerable distance blur to a still bothersome 2-3 lines ofdistance blur. Even instilled monocularly, pilocarpine still may createbothersome attendant distance blur and must be restricted to about 1.0%.Upon instillation of 1.0% pilocarpine pupil size is about 2.3 mm orlarger in most subjects and thereby restricts any significant pinholedepth perception benefit as well as any pinhole filtering of inducedmyopic rays. The restriction to about 1.0% for these conventionalformulations of pilocarpine with the attendant short duration and stillbothersome but reduced distance blur in emmetropes or myopes (somewhatneutralized in low hyperopes) are attempts to prevent extremely strongaccommodation of 5D to 11 D well known to occur at higher concentrationsof pilocarpine.

Any effects on accommodation may be further reduced or totallyeliminated in preferred embodiments by combining a miotic with acycloplegic agent in a narrow and particular ratio of miotic tocycloplegic, where such ratios as discovered for U.S. Pat. No. 9,089,562, such as about 35:1 for a preferred embodiment, become greatlyincreased for the present invention in the presence of cryoprotectant asto a factor of about 300%-700%. Aceclidine is capable of producing theincreased depth of focus by both pupil miosis below 2.3 mm and modestaccommodation described in the present invention. Particularly enhancedmiosis occurs with use of compositions of the present invention. Thisenhanced miosis makes it possible to use an α-2 agonist at very lowconcentrations if desired to reduce mild eye redness. Other combinationsof inactive ingredients reduce or effectively eliminate induced rednesswithout such agonists. Further, due to the apparent and surprisinglyselective nature of aceclidine, and the commercially stable aceclidineformulation discoveries of the present invention, administration to theeye of compositions of the present invention result in a net stronglyenhanced near vision acuity from both pupil miotic pinhole effect andmoderate modulated ciliary accommodation. These beneficial effects areaccompanied by a filtering pupil effect, which eliminates any distanceblur from the accommodation, correcting residual refractive error andoptical aberrations as may exist to in many cases improve distancevision as well. Thus, the administration of aceclidine results in pupilmiosis without excessive accommodation and attendant distance blur.However, aceclidine alone may cause substantial redness and brow ache.Without formulation enhancement of the present invention such asrequiring cycloplegic agent, cryoprotectant or b oth, aceclidine mayproduce either less than optimal pupil miosis at low concentrations orat higher concentrations require more than desired peak miosis to attainsatisfactory duration of greater than 3-4 hours. However the use of acycloplegic agent has been found to be highly sensitive to otherinactive ingredients in the formulation not usually associated witheffects on active agents, and particularly for cryoprotectants as foundto be preferred commercially for aceclidine reduce or eliminate the needfor this cycloplegic requirement to extremely low concentrations in apreferred embodiment, rendering 0.042% sufficiently high when acryoprotectant is present (e.g. a polyol such as mannitol) to causesubstantial loss of efficacy. Further, aceclidine without formulationenhancements of the present invention causes dimming of vision in dim orabsent lighting as well as ciliary pain above a reasonably tolerablethreshold that may last for an hour or more and be similar to a severemigraine headache.

Certain embodiments of the present invention enhance the discoveredpreferred degree of pupillary miosis by providing a consistent range ofeffect of about 1.50-2.20 mm for most patients using a preferredembodiment of a nonionic surfactant and viscosity agent. Similar benefitmay be achieved using other permeation enhancers, particularlyhydroxypropylmethyl cellulose, high viscosity carboxymethyl cellulose,Carbopol® (polyacrylic acid or carbomer), and various viscosityadditives that increase drug residence time, such as xanthan gums, guargum, alginate, and other in situ gels well known to experts in the art.It is well known to experts in the art that the exact concentration of aspecific viscosity agent will depend on both the molecular weight forthat agent selected and the concentration, such that for increasedmolecular weight a reduced concentration can have the same viscosity.The present invention further prevents nasal congestion otherwiseoccurring when substantial aceclidine levels reach the nasal mucosa, dueto the rheologic properties of the preferred embodiment.

The combination of aceclidine and a low concentration of a selective α-2adrenergic receptor agonist (α-2 agonist or α-2 adrenergic agonist),such as fadolmidine, brimonidine or guanfacine, allows for the desiredmiotic effect with diminished or no redness. The use of lowconcentrations of a selective α-2 agonist results in substantialreduction of hyperemia with greatly reduced risk of rebound hyperemiathat is found in concentrations of about 0.06% w/v or more. Furthermore,the use of low concentrations of selective α-2 agonist does notadversely modify the pupil constriction caused by aceclidine. Incontrast, the use of brimonidine 0.20% w/v, when topically applied forpupil modulation for night vision, result in tachyphylaxis of pupilmodulation due to α-2 receptor upregulation in almost 100% of treatedsubjects within four weeks of use.

Unexpectedly, the addition of a cycloplegic agent results in reductionof any brow ache or associated discomfort by further reducing the degreeof ciliary spasms on topical instillation without impairing the mioticresponse. More unexpectedly and surprisingly, the ratio of 1.40%aceclidine to about 0.040% tropicamide in a preferred embodiment of U.S.Pat. No. 9,089,562 (35:1) becomes about 1.75% aceclidine to about 0.004%to 0.010% tropicamide (350:1, 175:1 respectively) in the presence ofmannitol, where 2.5% provides better effect than 4.0%.

The lack of impairment of the miotic response is an unexpectedsurprising discovery, as particular cycloplegic agents, such astropicamide, have known pupil dilating effects at concentrations as lowas 0.01% w/v (Grunberger J. et al., The pupillary response test as amethod to differentiate various types of dementia, Neuropsychiatr, 2009,23(1), pg 57). More specifically cycloplegic agents cause pupilmydriasis (i.e. dilation of the radial muscle of the iris). Further, theaddition of a cycloplegic agent to the miotic agent unexpectedlyincreases the time at which the pupil maintains the desired size rangewithout becoming too restricted. Peak miotic effect at 30-60 minutes canbe titrated in inverse relation to the cycloplegic concentration. Theconcentrations of tropicamide discovered in the present inventionapparently cause more relaxation of the ciliary muscle than the irisradial musculature. In fact, iris mydriasis is discovered to besuppressed by the addition of tropicamide to compositions containingconcentrations of aceclidine used in the present invention, with insteada more consistent level of miosis for the duration of the miotic effect.Additionally and quite surprisingly, unexpectedly, and beneficially theaddition of tropicamide can reduce the degree of peak pupil miosiswithout inducing mydriasis thereby creating a more constant and idealpupil size throughout the drug induced miosis. This more consistentpupil size allows for beneficial near and distance vision without theadverse dimming or loss of resolution due to diffraction limits at thevery reduced pupil sizes seen at peak pupil miosis (e.g. 1.25 mm).

Previously, in U.S. Pat. No. 9,089,562, it was surprisingly found thatthe addition of at least 0.04% w/v cycloplegic agent resulted in anabatement of ciliary side effects caused by the administration ofaceclidine (1.40%) to the eye, in a preferred embodiment, but suchformulations are not as constituted sufficiently stable for commercialuse, and typically have a duration of about five to six hours maximum.

Several additional discoveries of the present invention allow forcommercially stable aceclidine formulations with enhanced efficacy andduration:

Equally or more surprising than the synergistic effects of cyloplegicsof 0.040% added to aceclidine 1.40%, is the discovery of the presentinvention that combination of aceclidine 1.50% −2.0%, and preferablyabout 1.75% and a cryoprotectant, preferably a polyol, in a preferredembodiment mannitol, particularly at 0.5% to 4.0% and most preferablyabout 2.5%, can achieve a similar pupil range with reduced or absentciliary side effects. The cryoprotectant when combined with aceclidinecan then be combined to allow lyophilization without degradation ofaceclidine and simultaneously further reduce or eliminate the need for acycloplegic agent for the present invention vs. the teachings ofcycloplegic concentration ranges required in U.S. Pat. No. 9,089,562.Optionally, the addition of a cryoprotectant can therefore also be usedto greatly reduce (i.e. no more than 0.025% w/v cycloplegic agent,preferably 0.004% to 0.015% and most preferably 0.005% to 0.010%) theconcentration of cycloplegic required to further eliminate mild, butpotentially bothersome, ciliary side effects particularly in youngerpresbyopes and further modulate pupil miosis over aceclidine and acryoprotectant combinations alone, reducing and in most caseseliminating any bothersome peak concentration dimming, as found inpreferred embodiments of the present invention. In preferred embodimentsit is discovered that aceclidine about 1.50%-2.0% and more preferably1.75% and mannitol about 0.5%-4.0% and more preferably 2.5% provideoptimal concentration combinations for the present invention, that arenecessary but not sufficient for about 3 lines of near improvement and 5or more hours duration desired for an effective topical presbyopiccomposition, where additional formulation discoveries can furtherenhance the desired clinical near improvement magnitude and duration;

It is surprisingly discovered that adding a viscosity agent tocompositions described in a. above only modestly improves magnitude andduration, however when first adding a nonionic surfactant, such aspolyoxyl stearate or polysorbate 80, optimal concentrations arediscovered that provide greatly improved magnitude and duration for thepresent invention, to which viscosity may then provide added durationmuch more substantially than when added alone. For polysorbate 80 orpolyoxyl 40 stearate concentrations of 1.0% to 10.0%, and morepreferably about 2.5% to 5.0% w/v have been found to be beneficial;

When formulation improvements of a. and b. above are combined, preferredembodiments such as aceclidine 1.75%, mannitol 2.5%, and polysorbate 802.75% result. Viscosity agents such as high viscosity carboxymethylcellulose (“CMC”) are surprisingly discovered to moderately enhancemagnitude and greatly enhance duration, unlike with formulations in a.above alone. High molecular weight CMC concentrations of 0.75% to 1.75%,and most preferably about 1.40%, or hydroxypropylmethyl cellulose(“HPMC”) at about 0.25% to 2.0%, more preferably about 0.50% or 1.50%,and most preferably about 1.0% to 1.25%, when combined result now inabout +3 lines of near vision improvement or greater, at a duration of5-10 hours, at a mean of about 7 hours or greater vs. pilocarpine 1.0%of about less than 4 hours;

Not wishing to be held to particular theory citrate in combination withEDTA as a preferred embodiment buffer appears to 1) reduce redness; 2)enhance sorbate preservative shelf life, and in combination of the abovewith BAK 0.005% to 0.02% (0.02% preferred) further enhances near visionlines to about 4 lines and duration to about 8 to 12 hours.

Additionally 0.5% or 1.5% sodium chloride is added in a preferredembodiment. Optionally, sodium chloride may be substituted with boricacid, preferably at 0.35% or potassium borate, preferably at 0.47%;

Not wishing to be held to particular theory, it appears the addition ofnonionic surfactant at optimized concentration of about 2.5% to 5.0%enhances permeation of aceclidine into the eye, which may relate tooptimal micellar size particularly once of micromicallar or nanomicellarrange. This increased permeation coincides with the desirable increasein magnitude and duration and absent tropicamide but in the presence ofmannitol with slight increases in ciliary sensation and dimming.Therefore in the presence of the combined formulation enhancements ofa-d. above, where a cycloplegic agent is no longer required for a-d.above, addition of a nonionic surfactant at concentrations found to bepreferred may be further improved with much lower concentrations of acycloplegic agent than those found in U.S. Pat. No. 9.089,562, such asthe use of about 0.042% tropicamide with aceclidine 1.40%. For thepresent invention then preferred embodiments include aceclidine of about1.75%, mannitol 2.5%, polysorbate 80 of about 2.5% to 5.0%, CMC of about1.42%, or HPMC of about 1.8% and tropicamide of about 0.004%-0.010%,more preferably about 0.005% to 0.007%, and most preferably about0.005%-0.006%. Micelle formation above the critical micellarconcentration may allow for micelles to spread across the tear filmsurface and spread at low concentrations to cover this surface, while athigher concentrations these micelles becoming increasingly contractedand “squeezed” along the surface. Not wishing to be held to particulartheory, it is believed at an optimal concentration a minimal micellediameter is achieved before significant multiple lamellae (layering)occurs. It is believed that the optimal concentration nanomicelles ofabout 100 to 250 nm along the surface are achieved surrounding thehighly charged and hydrophilic aceclidine, facilitating its penetrationthrough the very lipophilic epithelium;

Not wishing to be held to particular theory the addition of BAK 0.02% tosorbate about 0.10%, EDTA about 0.10%, in a preferred composition ofaceclidine 1.75%, mannitol 2.5%, tropicamide 0.01%, and citrate buffer(1 to 100 mM 3-5 mM preferred) is above the BAK critical micellarconcentration. BAK, being a cationic surfactant, and BAK micelles,creating an ionic micellar gradient with + charge NH4+ quaternarynitrogen bring on the polar heads aggregating outside and lipophilicalkyl chain on the hydrophobic tails aggregating on the inside may causesignificant similar aceclidine alignment due to its dipole withquaternary NH3 nucleophilic or NH4 protonated nitrogens oriented alongthe outside polar heads and more hydrophobic carbonyls C═O alonghydrophobic BAK micellar tails these preventing, greatly reducing, ormoderately reducing collisions of any nonionic aceclidine molecules—thenucleophiles—which if oriented in solution such that randomly theycollide with another aceclidine carbonyl will result in chemicalconversion of that aceclidine via nucleophilic attack at its targetedcarbonyl, which can recur from such nucleophiles to other aceclidines sooriented repeatedly and cause loss of stability without such BAKorientation via 0.005% and preferably 0.01% to 0.02% most preferredmicelles. The concentration of such nonionic nucleophiles at a preferredpH in the preferred embodiment is relatively low, but the ability ofthese nonionic nucleophiles to destabilize adjacent aceclidinesrepeatedly without themselves degrading is otherwise high. The resultmay be improved potency for 1 month plus of a mixed solution once openedin a dual chamber bottle and mixing occurs of lyophilizedaceclidine/mannitol with the remainder of the formulation in the diluentand or improved stability sufficient for commercialization in solution,either at room temperature or via cold chain;

It is discovered that BAK alone does not provide sufficient bacterialand fungal preservative efficacy but that BAK and sorbate, or sorbatealone satisfactorily preserve diluent and or mixed solutions of theinvention;

Not to be wishing to be held to particular theory preferred embodimentsof the present invention such as containing 1.25% hydroxypropyl methylcellulose may have a viscosity of about 400 cps prior to instillation,yet unlike conventional high viscosity artificial tear formulations suchas Celluvisc® at about 400 cps, which may blur vision for 10-20 minutesor Liquigel® at about 100 cps, which causes similar but slightly reducedblurring causes only about 60 seconds of blur dissipating rapidly withan influx of tear secretion; where both a nonnewtonian reduction inviscosity at high shear (such as about 1/1000 sec during a blink, andaceclidine parasympathetic trigger of tear secretion as a sialogen maycontribute.

General miotic agents, such as pilocarpine, carbachol and phospholinediesterase, are capable of causing pupil miosis resulting in improvednear vision of presbyopic patients. However, there is an inversereduction in distance vision associated with these general miotic agentsfrom miosis at peak effect and accommodation that is not seen withaceclidine. The co-administration of a cycloplegic agent with aceclidinesurprisingly results in an attenuation of this reduction in distancevision.

Comfort, safety, and efficacy of a preferred embodiment of anophthalmological composition of the present invention results from thepresence of a nonionic surfactant, such as cyclodextrin alpha, beta, orgamma chains, preferably 2-hydroxypropyl beta-cyclodextrin (“HPβCD”),and, sulfobutyl ether derivative of β-cyclodextrin (Captisol®), apolyoxyl alkyl such as polyoxyl 40 stearate and polyoxyl 35 castor oil,or a poloxamer such as poloxamer 108 and poloxamer 407, a polysorbatesuch as polysorbate 80 or Brij® 35(Brij is a registered trademark ofUniqema Americas LLC); a viscosity enhancing agent, such ascarboxymethyl cellulose (“CMC”); a tonicity adjustor, such as sodiumchloride; a preservative, such as benzalkonium chloride and a pH fromabout 5.0 to about 8.0. Further, an increase in the concentration of thenonionic surfactant may result in reduced redness. Specifically,increasing polysorbate from 0.10% to 0.50-1.0% results in reducedredness. Further, increasing CMC or Carbopol® 940 from 0.50% to 1.5% w/v(preferably 1.40-1.43% w/v) results in enhanced near vision, bothquantitative improvement and duration improvement.

The viscosity of compositions of the present invention comprising aviscosity agent may be from about 1 to about 10,000 cps prior to topicalinstillation in the eye. As a result of the shear force applied to thecomposition as it exits the device used for administration the viscosityis lowered to a range from about 1 to about 25 cps at the high shear ofblinking, and 50 cps to 200 cps at the low shear between blinks,allowing greater drop retention with less spillage and less nasolacrimaldrainage and systemic absorption upon topical instillation.

In one embodiment, the present invention is directed to anophthalmological composition comprising aceclidine. In a preferredembodiment, aceclidine is at a concentration from about 0.25% to about2.0% w/v, more preferably from about 0.50% to about 1.90% w/v, stillmore preferably from about 1.65% to about 1.85% w/v, and most preferablyabout 1.75% w/v. As aceclidine is a tertiary amine with asymmetry, botha + and − optical isomer exist (where in some studies (+) is more potentand in others it is felt (−) may be more potent). For the aboveconcentrations polarimetry demonstrated an exactly equal ratio of (+)and (−) isomer for these concentrations. Altering this ratio couldtherefore alter this concentration range proportional to a change inratio.

It is a discovery of the present invention that several modificationsmay singly or in combination be used to enhance cold chain stabilitystorage, including in addition to in a preferred embodiment aceclidine1.40%-1.75%, tropicamide 0.025%-0.10% and optionally a nonioinicsurfactant such as polyoxyl 40 stearate 0.5%-10%, preferably 5.5% one ormore of (See Table 1):

Acidic pH, preferably less than 5.5, preferably less than 5.0 and mostpreferably at a pH of about 4.75;

Viscosity agent, preferably at 25C viscosity of about 15-50 cps, andmore preferably 20-45 cps, where a preferred embodiment is carbomer 9400.09%-1.5%;

Addition of a cryoprotectant, in a preferred embodiment a polyol,preferably Mannitol 2.5%-4.0%;

Addition of a buffer, where acetate or phosphate buffers are preferred,2-100 mmole range with 3-5 mmole is preferred; and

Addition of a preservative, where BAK 0.015% is preferred.

Muscarinic Agonists

The present invention is further directed to an ophthalmologicalcomposition comprising a muscarinic agonist, preferably a nonionicsurfactant above its critical micellar concentration for thecomposition, and a viscosity enhancing agent; or alternatively an insitu gelling agent. In preferred embodiments the initial viscosity ofthe composition on topical application is above 20 cps, preferably 50cps, and more preferably above 70 cps at low shear (1/s).

Muscarinic agonists include selective α-2 agonists, which may beincluded within the composition of the present invention or appliedtopically preferably just minutes before or less preferably just minutesafterward if additional means to reduce nasal congestion or redness isdesired for sensitive subjects. Selective α-2 agonists suitable for thepresent invention have minimal α-1 agonist activity at lowconcentrations. For example, for brimonidine or fadolmidine, 1% to 2%w/v is considered extremely high, 0.5% to 1.0% w/v still highlyinductive of α-1 receptors and toxic for purposes of the presentinvention. Further, 0.10% to 0.5% w/v is still too high and even 0.070%to 0.10% w/v is associated with a higher than preferred incidence ofrebound hyperemia (however, for dexmedetomidine, its greaterlipophilicity and intraocular penetration reduces rebound risk in thisrange). Only 0.065% w/v or below is potentially acceptable, where formost α-2 agonists, depending on degree of selectivity 0.050% w/v or evenmore preferably 0.035% w/v or less is desired. On the other hand somedegree of useful activity may occur at one or more orders of magnitudefurther reduction of concentration. The preferred embodiments,brimonidine, fadolmidine and guanfacine, of the present inventionpreferentially stimulate α-2 adrenergic receptors, and even morepreferably α-2b adrenergic receptors so that α-1 adrenergic receptorsare not stimulated sufficiently enough to cause excessive large vesselarteriolar constriction and vasoconstrictive ischemia. In addition, ithas been discovered that preventing or reducing redness for drugs thatotherwise directly induce redness, such as the acetylcholine agonist,aceclidine, enhances compliance for sensitive subjects that may haveinduced redness or nasal congestion even with formulations of thepresent invention that do not include an α-2 agonist. However, becauseα-2 agonists are shifted to their ionized equilibrium an acidic pH issomewhat offset by the fact such agonists exert greater affect atneutral or alkaline pH. Therefore each α-2 agonist has a preferred pHrange depending on its lipophilicity and pKa value when added to theinventive compositions with aceclidine. For the present invention whilepH range of 5.0 to 8.0 is tolerated, preferred embodiments are at pH 5.5to 7.5 and more preferably 6.5 to 7.0. Further, it has been discoveredthat cyclodextrins and/or polyoxyl 40 stearate as a nonionic surfactantcomponent or as the sole nonionic surfactant, result in a greaterwhitening effect when the α-2 agonist is included in the compositionrather than poloxamer 407. The α-2 agonist may optionally be appliedseparately or in certain preferred embodiments with formulations of thepresent invention that do not include an α-2 agonist, such as thoseformulas with polyoxyl 40 stearate 5.5% w/v as the non-ionic surfactant,although the α-2 agonist is not required except for occasional sensitivesubjects. Fad olmidine represents the α-2 agonist with highesthydrophilicity and therefore high surface retention for the presentinvention. Guanfacine is also highly selective and hydrophilic.Brimonidine is highly selective with moderate lipophilicity. Finally,dexmedetomidine has high selectivity with high lipophilicity that may beused with less efficacy for reducing redness for the purposes of thepresent invention (although possibly inducing fatigue as a side effectin some patients). In a preferred embodiment using polyoxyl 40 stearate5.5% w/v; CMC 0.80% w/v; NaCl 0.037% w/v; ethylenediaminetetraaceticacid (“EDTA”) 0.015% w/v, borate buffer 5 mM and BAK 0.007% w/v resultsin redness of about 1.0 to 1.5 out of 4 which is transient lasting aboutten minutes, and by 30 minutes returns to about baseline.

In one embodiment, the selective α-2 adrenergic receptor agonist is acompound which has binding affinity of about 900 fold or greater, evenmore preferably about 1000 fold or greater, and most preferably, about1500 fold or greater.

The selective α-2 adrenergic receptor agonist may be present at aconcentration from between about 0.0001% to about 0.065% w/v; morepreferably, from about 0.001% to about 0.035% w/v; even more preferably,from about 0.01% to about 0.035% w/v; and even more preferably, fromabout 0.020% to about 0.035% w/v.

In one embodiment, the selective α-2 adrenergic receptor is selectedfrom the group consisting of brimonidine, guanfacine, fad olmidine,dexmedetomidine,(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.Analogues of these compounds that function as highly selective α-2agonists may also be used in compositions and methods of the presentinvention.

In a more preferred embodiment, the selective α-2 agonist is selectedfrom the group consisting of fad olmidine, guanfacine and brimonidine.In a yet more preferred embodiment the selective α-2 agonist isbrimonidine in the form of a salt at a concentration of 0.025% to 0.065%w/v, more preferably from 0.03% to 0.035% w/v. In a preferredembodiment, the salt is a tartrate salt.

In another yet more preferred embodiment, the selective α-2 agonist isfadolmidine at a concentration from about 0.005% to about 0.05% w/v,more preferably from 0.02% to about 0.035% w/v in the form of ahydrochloride (“HCl”) salt.

In another yet more preferred embodiment, the selective α-2 agonist isguanfacine at a concentration from about 0.005% to about 0.05% w/v, morepreferably from 0.02% to about 0.035% w/v in the form of an HCl salt.

In another yet more preferred embodiment, the selective α-2 agonist isdexmedetomidine at a concentration from about 0.005% to about 0.05% w/v,more preferably from 0.04% to about 0.05% w/v in the form of an HClsalt.

In another preferred embodiment a pH less than physiologic pH is foundto enhance the whitening effect for brimonidine, preferably pH 4.5 to6.5, and more preferably pH 5.5 to 6.0. However, redness reduction isachieved at all pHs, and enhancement of aceclidine absorption occurs atalkaline pH, such that more effect occurs from a given concentration,and therefore while effective at pH ranges from 4.5 to 8.0, pH range of6.5 to 7.5 is preferred for the present invention, and 7.0 to 7.5 mostpreferred.

The present invention is further directed to an ophthalmologicalcomposition comprising a muscarinic agonist and further comprising acycloplegic agent. It is a surprising and totally unexpected discoveryof the present invention that certain cycloplegic agents can be combinedwith miotic agents, particularly for the present invention, aceclidine,without reducing miotic onset, magnitude, or duration; and further bluntthe normally attendant spike in miotic effect coinciding with time ofpeak absorption in aqueous formulations to provide a constant miosisversus time after onset from 15 to 30 minutes to 6 to 10 hours dependingon the desired formulation. The addition of the cycloplegic agent alsoreduces any residual associated discomfort that may otherwise occur soonafter topical instillation, which presumably is a result of ciliaryspasms or excessive pupillary miosis.

Cycloplegic agents suitable for the present invention include, but arenot limited to, atropine, Cyclogyl® (cyclopentolate hydrochloride),hyoscine, pirenzepine, tropicamide, atropine,4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), AF-DX 384,methoctramine, tripitramine, darifenacin, solifenacin (Vesicare),tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium (Spriva),and otenzepad (a.k.a. AF-DX 116 or11-{[2-(diethylamino)methyl]-1-piperidinyl}acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepine-6-one).In a preferred embodiment the cycloplegic agent is tropicamide at aconcentration from about 0.004% to about 0. 025% w/v, more preferablyfrom about 0.005% to about 0.015% w/v and still more preferably fromabout 0.005% to about 0.011% w/v, from about 0.005% to about 0.007% w/vand from about 0.005% to about 0.006% w/v. In another preferredembodiment the cycloplegic agent is a mixture of tropicamide at aconcentration from about 0.04% to about 0.07% w/v or pirenzepine orotenzepad at a concentration from about 0.002% to about 0.05% w/v.

In a preferred embodiment, tropicamide 0.01% w/v was found to slightlyreduce brow ache, 0.030% w/v to further reduce brow ache and from 0.04%to about 0.07% w/v to completely eliminate brow ache without reductionof the average pupillary miosis diameter over duration of effect.Tropicamide in preferred embodiments has demonstrated completelyunexpected sensitivity of effect, where at about 0.04% w/v unexpectedlyand very effectively reduces or eliminates brow ache and ciliary spasmpain, becoming very noticeably further reduced at 0.042% w/v and absentat 0.044% w/v in a preferred embodiment with no cycloplegia (surprisingdue to its common use as a pupil dilating agent). Yet, tropicamide didnot reduce the mean degree of pupil miosis, the time of onset of pupilmiosis or the subsequent visual benefits. On the contrary, tropicamideblunted the peak miosis seen in aqueous formulations to create a smoothconsistent miotic effect over time. It allowed modulation of peak pupilmiosis to achieve a more even effect over time with no dilation as hasbeen found with its prior use. Specifically, tropicamide is useful toprevent transient constriction below 1.50 mm at 30 to 60 minutesfollowing aceclidine in some embodiments and to reduce transientexcessive and undesirable dimming of vision that may otherwise occur atpeak onset of about 30 minutes. As an example, an ophthalmologicalcomposition comprising 1.53% w/v aceclidine, 5% w/v HPβCD, 0.75% w/vCMC, 0.25% w/v NaCl, 0.01% w/v BAK and a phosphate buffer at pH 7.0; or1.45% w/v aceclidine; 5.5% w/v polyoxyl 40 stearate; 0.80% w/v CMC;0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK and 5mM phosphatebuffer at a pH 7.0; was varied from 0.040% w/v tropicamide, wheremoderate dimming was noted, to 0.044% w/v tropicamide where dimmingbecame almost undetectable other than in extremely dim light conditions.This additional pupil size modulation with a cycloplegic agent allowsaceclidine concentrations sufficient for prolonged effect while bluntingthe attendant peak excessive constriction that is undesirable as well asany uncomfortable brow ache. Surprisingly and due to its short-actingnature, tropicamide achieves this blunting effect without causingmydriasis. Further, in a preferred embodiment, tropicamide 0.014% w/vwas found to reduce brow ache, 0.021% w/v to further reduce brow acheand from 0.028% to 0.060% w/v and in some embodiments up to 0.09% w/v tocompletely eliminate brow ache without cycloplegia (i.e. paralysis ofciliary muscle of the eye).

It has been found for a racemic 50:50 mixture of (+) and (−) aceclidineoptical isomers (where in some studies (+) is more potent and in othersit is felt (−) may be more potent) tropicamide effects may varydepending on the ratio of aceclidine to tropicamide. For example, in anophthalmological composition of the present invention comprising 1.55%w/v aceclidine, 5.5% w/v HPβCD or in a preferred embodiment polyoxyl 40stearate, 0.75% w/v CMC (1%=2,500 centipoise), 0.25% w/v NaCl, and 0.01%w/v BAK and at pH 7.5, 0.042% w/v tropicamide can be differentiated fromeven 0.035% w/v, with the former demonstrating normal indoor nightvision and the latter slight dimming that becomes more noticeable atstill lower concentrations.

At higher concentrations, such as from about 0.075% to about 0.090% w/vtropicamide, loss of optimal range pupil constriction 1.50 mm to 1.80 mmrange begins, and frank mydriasis at higher concentrations begins tooccur. As isomer ratio may alter the effective concentration, this mustbe factored into the clinical efficacy anticipated using aceclidine; forpreferred embodiments of the present invention a polarimeter was used todetermine an exact 50:50 isomer ratio was used (personal communicationToronto Research Chemicals).

FIG. 1 shows the effect of a miotic agent with or without a cycloplegicagent and with or without a carrier. Subject is an emmetrope over theage of 45 with a baseline near vision of 20.100 and baseline distancevision of 20.20. Topical administration to the eye of 1% w/v pilocarpinein saline solution results in an improvement of near vision to 20.40(8a), however this improvement comes at the expense of a reduction indistance vision to 20.100 (8b). The addition of 0.015% w/v tropicamideresults in an improvement of near vision to 20.25 (9a) and a lesseningof the reduction of distance vision to 20.55 (9b), though in certaininstances with some induced irregular astigmatism (mildly blotched areasin reading field of vision). Topical administration of 1.55% w/vaceclidine in saline solution results in an improvement of near visionto 20.40 for an extended time period of 6 hrs (10a) without any effecton the baseline distance vision (10b). 10c and 10d show the effects ofadministering aceclidine in a carrier composed of 5.5% w/v2-hydroxypropyl beta cyclodextrin, 0.75% w/v CMC (1%=2,500 centipoise),0.25% w/v NaCl, and 0.01% w/v BAK. As seen in 10c the carrier increasesthe beneficial effect of aceclidine resulting in better than 20.20 nearvision. As seen in 10d a similar increase in distance vision occurs. 10eand 10f show the effects of adding 0.042% w/v tropicamide to theaceclidine in the carrier. As seen in 10e near vision is improved to20.15 with a quicker onset of maximum visual acuity. As seen in 10f asimilar improvement is seen in distance vision. Taken together, FIG. 1shows that aceclidine is capable of temporarily correcting near visionin a presbyopic subject without affecting the baseline distance vision.Similar results can be achieved with a different miotic agent,pilocarpine, with the addition of a cycloplegic agent such astropicamide. A proper drug carrier can also have a beneficial effect.

It is a surprising and unexpected discovery that topical formulations ofthe present invention, particularly one of the preferred embodimentscomprising aceclidine 1.35% to 1.55% w/v; 5.5% w/v polyoxyl 40 stearate;0.80% w/v CMC; 0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK; and 5mMphosphate buffer at pH 7.0 result in considerably prolonged contact lenswear and comfort after a single topical instillation daily. The singledaily use of the preferred embodiments allowed a subject with dry eye tosleep in his lenses for one week periods where previously even after asingle night vision would be blurred and contact lenses coated with filmrequiring removal and cleaning or replacement (see Example 7).

In preferred embodiments, an ophthalmological composition of the presentinvention comprises aceclidine, a cryoprotectant, optionally acycloplegic agent, a nonionic surfactant at a concentration from about1% to about 5% w/v and a viscosity agent at a concentration of about0.75% to about 1.6% w/v, preferably about 1.25% to about 1.5% w/v.

The following representative embodiments are provided solely forillustrative purposes and are not meant to limit the invention in anyway.

REPRESENTATIVE EMBODIMENTS

In one embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v; and-   mannitol at a concentration of about 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   mannitol at a concentration of about 2.5% w/v; and-   tropicamide at a concentration of about 0.02% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 5.0% w/v;-   carboxymethyl cellulose at a concentration of about 1.4% w/v;-   BAK at a concentration of about 0.015% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM,-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 0.5% w/v;-   NaCl at a concentration from about 0.10% to about 0.50% w/v;

Carbopol® 940 at a concentration of about 0.95% w/v;

-   BAK at a concentration of about 0.01% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM,-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 2.0% w/v;-   NaCl at a concentration of about 0.50% w/v-   Carbopol® 940 at a concentration of about 1.5% w/v;-   BAK at a concentration of about 0.015% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM,-   wherein the pH is about 5.25.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 0.25% w/v;-   NaCl at a concentration of about 0.1% w/v;-   boric acid at a concentration of about 0.12% w/v;-   Carbopol® 940 at a concentration of about 0.95% w/v; and-   BAK at a concentration of about 0.015% w/v;-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 0.50% w/v;-   NaCl at a concentration of about 0.05% w/v;-   boric acid at a concentration of about 0.2% w/v;-   Carbopol® 940 at a concentration of about 0.95% w/v;-   BAK at a concentration of about 0.01% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM,-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 0.1% w/v;-   boric acid at a concentration of about 0.2% w/v;-   Carbopol® 940 at a concentration of about 0.9% w/v;-   BAK at a concentration of about 0.05% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM,-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 0.1% w/v;-   NaCl at a concentration of about 0.1% w/v;-   boric acid at a concentration of about 0.12% w/v;-   Carbopol® 940 at a concentration of about 0.95% w/v;-   BAK at a concentration of about 0.01% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM,-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   tropicamide at a concentration of about 0.01% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 5.0% w/v;-   CMC at a concentration of about 1.4% w/v;-   BAK at a concentration of about 0.015% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM,-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   tropicamide at a concentration of about 0.02% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 0.25% w/v;-   NaCl at a concentration of about 0.1% w/v;-   boric acid at a concentration of about 0.12% w/v;-   Carbopol® 940 at a concentration of about 0.95% w/v; and-   BAK at a concentration of about 0.01% w/v.-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   tropicamide at a concentration of about 0.015% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 0.75% w/v;-   NaCl at a concentration of about 0.05% w/v;-   boric acid at a concentration of about 0.2% w/v;-   Carbopol® 940 at a concentration of about 0.95% w/v;-   BAK at a concentration of about 0.01% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM.-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   tropicamide at a concentration of about 0.025% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 0.1% w/v;-   boric acid at a concentration of about 0.2% w/v;-   Carbopol® 940 at a concentration of about 0.9% w/v;-   BAK at a concentration of about 0.05% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM.-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   tropicamide at a concentration of about 0.02% w/v;-   mannitol at a concentration of about 2.5% w/v;-   polysorbate 80 at a concentration of about 0.1% w/v;-   NaCl at a concentration of about 0.1% w/v;-   boric acid at a concentration of about 0.12% w/v;-   Carbopol® 940 at a concentration of about 0.95% w/v;-   BAK at a concentration of about 0.01% w/v; and-   optionally, phosphate buffer at a concentration of about 3 mM.-   wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.75% w/v;-   tropicamide at a concentration of about 0.040% w/v;-   polyoxyl 40 stearate at a concentration of about 5.0% w/v;-   mannitol at a concentration of about 2.5% w/v;-   optionally, acetate or phosphate buffer at a concentration of about    3.0 mM; and-   BAK at a concentration of about 0.01% w/v,-   wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.55% w/v;-   tropicamide at a concentration of about 0.040% w/v;-   polyoxyl 40 stearate at a concentration of about 5.0% w/v;-   citric acid monohydrate at a concentration of about 0.1% w/v;-   mannitol at a concentration of about 4.0% w/v;-   Carbopol® 940 at a concentration of 0.09% w/v; and-   optionally, acetate or phosphate buffer at a concentration of about    3.0 mM;-   wherein said composition has a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.50% w/v;-   tropicamide at a concentration of about 0.042% w/v;-   polyoxyl 40 stearate at a concentration of about 5.5% w/v;-   mannitol at a concentration of about 2.5% w/v;-   optionally, phosphate buffer at a concentration of about 3.0 mM;-   Carbopol® 940 at a concentration of about 0.85% w/v; and-   BAK at a concentration of about 0.01% w/v,-   wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.45% w/v;-   tropicamide at a concentration of about 0.042% w/v;-   polyoxyl 40 stearate at a concentration of about 5.5% w/v;-   citric acid monohydrate at a concentration of about 0.1% w/v;-   optionally, acetate buffer at a concentration of about 3.0 mM; and-   Carbopol® 940 at a concentration of about 0.75% w/v,-   wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of about 1.45% w/v;-   tropicamide at a concentration of about 0.042% w/v;-   polyoxyl 40 stearate at a concentration of about 5.5% w/v;-   mannitol at a concentration of about 2.0% w/v;-   citric acid monohydrate at a concentration of about 0.1% w/v;-   optionally, phosphate buffer at a concentration of about 3.0 mM; and-   Carbopol® 940 at a concentration of about 1.0% w/v,-   wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 2.5% w/v mannitol;-   about 2.75% w/v polysorbate 80; and-   about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl cellulose (depending    on its molecular weight).

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 0.005% to about 0.011% tropicamide;-   about 2.5% w/v mannitol;-   about 2.75% w/v polysorbate 80; and-   about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl cellulose (depending    on its molecular weight).

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 0.010% w/v tropicamide;-   about 2.5% w/v mannitol;-   about 5.0% w/v polysorbate 80;-   about 1.40% w/v carboxymethyl cellulose high viscosity;-   optionally, about 3 mM phosphate buffer; and-   about 0.010% BAK=as preservative,-   with a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 0.006% w/v tropicamide;-   about 2.5% w/v mannitol;-   about 2.5% w/v polysorbate 80;-   about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl cellulose (depending    on its molecular weight);-   optionally, about 3 mM phosphate buffer; and-   about 0.020% BAK=as preservative,-   with a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 0.006% w/v tropicamide;-   about 2.5% w/v mannitol;-   about 2.5% w/v polysorbate 80;-   about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl cellulose (depending    on its molecular weight);-   optionally, about 3 mM phosphate buffer;-   about 0.50% w/v NaCl; and-   about 0.020% BAK=as preservative,-   with a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 2.5% w/v mannitol;-   about 3.5% w/v polysorbate 80;-   about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl cellulose (depending    on its molecular weight);-   optionally, about 3 mM phosphate buffer;-   about 0.50% w/v NaCl; and-   about 0.020% BAK or 0.15% sorbic acid as preservative,-   with a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 2.5% w/v mannitol;-   about 3.5% w/v polysorbate 80; and-   about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl cellulose (depending    on its molecular weight);-   In another embodiment, the ophthalmological composition comprises:-   about 1.75% w/v aceclidine;-   about 2.5% w/v mannitol;-   about 3.5% w/v polysorbate 80;-   about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl cellulose (depending    on its molecular weight); and-   one or more excipient selected from the group consisting of about    0.50% w/v sodium chloride, about 0.02% w/v benzalkonium chloride,    about 0.10% w/v sorbate, about 0.01% w/v ethylenediaminetetraacetic    acid (EDTA) and 0.10% w/v citric acid.

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 2.5% w/v mannitol;-   about 0.01% w/v tropicamide;-   about 0.1% w/v sodium citrate, anhydrous;-   about 0.02% w/v benzalkonium chloride;-   about 0.12% w/v sorbic acid;-   about 0.1% w/v disodium edetate dihydrate;-   about 4.0% w/v polysorbate 80; and-   about 1.25% w/v hydroxypropylmethyl cellulose,-   wherein the pH is about 5.0.

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 2.5% w/v mannitol;-   about 0.01% w/v tropicamide;-   about 0.1% w/v sodium citrate, anhydrous;-   about 0.02% w/v benzalkonium chloride;-   about 0.1% w/v sorbic acid;-   about 0.1% w/v EDTA;-   about 3.5% w/v polysorbate 80; and-   about 1.25%; 1.0%-2.25% w/v hydroxypropylmethyl cellulose (depending    on its molecular weight),-   wherein the pH is about 5.0.

In another embodiment, the ophthalmological composition comprises:

-   about 1.75% w/v aceclidine;-   about 2.5% w/v mannitol;-   about 0.01% w/v tropicamide;-   optionally, about 3mM phosphate buffer;-   about 0.02% w/v benzalkonium chloride;-   about 0.1% w/v sorbic acid;-   about 0.1% w/v citrate;-   about 3.5% w/v polysorbate 80; and-   about 1.25%; 0.25%-2.25% w/v hydroxypropylmethyl cellulose    (depending on its molecular weight);-   wherein the pH is about 5.0.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of 1.5% w/v, mannitol at a    concentration of 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of 1.55% w/v, mannitol at a    concentration of 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of 1.6% w/v, mannitol at a    concentration of 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of 1.65% w/v, mannitol at a    concentration of 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of 1.7% w/v, mannitol at a    concentration of 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of 1.75% w/v, mannitol at a    concentration of 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of 1.80% w/v, mannitol at a    concentration of 2.75% w/v and Carbopol® 940 at a concentration of    0.09% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of 1.48% w/v, mannitol at a    concentration of 1.5% w/v and Carbopol® 940 at a concentration of    0.50% w/v.

In another embodiment, the ophthalmological composition comprises:

-   aceclidine at a concentration of 1.80% w/v, mannitol at a    concentration of 2.5% w/v and Carbopol® 940 at a concentration of    0.9% w/v.

In certain preferred embodiments, the present invention is directed tocompositions for the treatment of presbyopia comprising about 1.75% w/waceclidine, about 4.0% w/w polysorbate 80, about 2.5% w/w mannitol,about 1.2% w/w hydroxypropylmethyl cellulose, about 0.1% w/wethylenediaminetetraacetic acid, about 0.02% w/w benzalkonium chloride,about 0.12% w/w potassium sorbate and about 0.077% w/w citrate, whereinthe composition has a pH of about 5.0.

In certain preferred embodiments, the present invention is directed tocompositions for the treatment of presbyopia comprising about 1.75% w/waceclidine, about 4.0% w/w polysorbate 80, about 2.5% w/w mannitol,about 1.2% w/w hydroxypropylmethyl cellulose, about 0.1% w/wethylenediaminetetraacetic acid, about 0.02% w/w benzalkonium chloride,about 0.12% w/w potassium sorbate and about 0.1% w/w citrate, whereinthe composition has a pH of about 5.0.

In certain preferred embodiments, the present invention is directed tocompositions for the treatment of presbyopia comprising about 1.40% w/waceclidine, about 2.0% w/w polyoxyl stearate, about 2.5% w/w mannitol,about 0.1% w/w ethylenediaminetetraacetic acid, about 0.02% w/wbenzalkonium chloride, about 0.12% w/w potassium sorbate and about 0.1%w/w citrate, wherein the composition has a pH of about 5.0.

The following Examples are provided solely for illustrative purposes andare not meant to limit the invention in any way.

EXAMPLES Example 1 Effect of Aceclidine on Vision of Subjects Aged 47 to67 Years

Table 1 demonstrates the effect on the near focus ability of presbyopicsubjects before and after ophthalmological administration of acomposition containing aceclidine. Each composition included aceclidinein the concentrations indicated and 5.5% w/v HPβCD, 0.75% w/v CMC, 0.25%w/v NaCl and 0.01% w/v BAK. Additionally compositions administered tosubjects 4 and 5 included 0.125% w/v tropicamide. As aceclidine is anenantiomer, the clinical effectiveness may vary with different ratios.For the present studies a nearly exact 50:50 ratio of stereoisomers wasmeasured as best determined by polarimetry.

TABLE 1 Effects of aceclidine on vision of presbyopic patients. VisionBaseline Post Gtt 15″ Aceclidine R Pre L Pre R Pre L Pre R Post L Post RPost L Post Effect Date # Age % Dist Dist Near Near Dist Dist Near Near(h) Aug. 21, 2013 1 67 1.5 20.20 20.30 20.60 20.60 20.20 20.20 20.1520.15 9.00 Aug. 22, 2013 2 52 1.5 20.30 20.30 20.50 20.50 20.25 20.2520.25 20.20 8.00 Aug. 23, 2013 3 61 1.5 20.40 20.30 20.60 20.50 20.2020.25 20.15 20.15 8.00 Aug. 23, 2013 4 61 1.1 20.20 20.25 20.80 20.5020.15 20.15 20.20 20.15 12.00 Aug. 23, 2013 5 53 1.1 20.20 20.20 20.6020.60 20.20 20.20 20.25 20.25 7.00 Aug. 24, 2013 6 47 1.5 20.25 20.2520.100 20.100 20.20 20.20 20.15 20.15 8.00 Aug. 25, 2013 7 58 1.5 20.3020.200 20.100 20.30 20.25 20.30 20.20 20.30 8.00

As seen in Table 1 all subjects had less than perfect near vision(20.20) in both the left and right eye (object at 15 inches from theeye) and most subjects had less than perfect distance vision beforeadministration of the composition. After administration of thecomposition all subjects experienced an improvement in their near visionthat lasted from 7 to 12 hours. Surprisingly, the majority of subjectsalso experienced improvement of their distance vision for the same timeperiod. Still more surprisingly the improvement in near point was muchcloser than 16″ typically required for comfortable reading, in somecases to about 8.5″ more commonly seen in individuals 30 or less. Theaddition of tropicamide, a cycloplegic agent, had no additive ordeleterious effect on vision correction.

Example 2 Effect of Concentration of Concentration of Aceclidine andTropicamide

TABLE 2 Effect of concentration of concentration of aceclidine andtropicamide. #1 #2 #3 #4 #5 (OD) #5 (OS) #6 #7 Brimonidine 0.03% 0.03%0.03% 0.03% 0.03% 0.03% 0.03% Poloxamer 407  5.5% HPBCD  5.5%  5.5% 5.5%  5.5%  5.5%  5.5%  5.5% Aceclidine  1.5%  1.5% 0.75%  1.1%  1.1% 1.1%  1.1%  1.1% Tropicamide 0.014%  0.021%  0.028%  0.042%  0.062% NaCl 0.25% 0.25% 0.25% 0.25% 0.25% 0.75% 0.25% 0.25% CMC 0.75% 0.75%0.75% 0.75% 0.75% 0.75% 0.75% 0.75% BAK  0.1%  0.1%  0.1%  0.1%  0.1% 0.1%  0.1%  0.1% Redness (15 m)  3+  1   0.5 0.5 0 0 0 0 Redness (30 m)1.5 0.5 0.25 0.25 0 0 0 0 Brow Ache (60 m)  2+   2+  2 0.5 0.5 0.0 0.00.0 Stinging (10 m) 2   2   0.5 0 0 0 0 0 BD-OD 20.20 20.20 20.20 20.2020.20 20.20 20.20 20.20 BD-OS 20.25 20.25 20.25 20.25 20.25 20.25 20.2520.25 BN-OD 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt BN-OS 7 pt 7 pt 7 pt7 pt 7 pt 7 pt 7 pt 7 pt BP-photopic   3 mm   3 mm 3 mm   3 mm   3 mm  3 mm   3 mm   3 mm BP-mesopic   5 mm   5 mm 5 mm   5 mm   5 mm   5 mm  5 mm   5 mm Miosis start (m) 15   15   15 15 15 15 15 15 Miosis (OU)(1 hr) 1.63 mm 1.63 mm 2.0-2.5 mm 1.63 mm 1.63 mm 1.63 mm 1.63 mm 1.70mm Distance (OD) (20 m) 20.20 20.20 20.20 20.20 20.20 20.20 20.20 20.20Distance (OD) (1 hr) 20.15 + 2 20.15 + 2 20.20 20.15 + 2 20.15 + 220.15 + 2 20.15 + 2 2015 + 2 Distance (OS) (1 hr) 20.15 + 2 20.15 + 220.20 20.15 + 2 2015 + 2 20.15 + 2 20.15 + 2 20.15 + 2 Disance (OU) (1hr) 20.10 − 3 20.10 − 3 20.15 20.10 − 3 20.10 − 3 20.10 − 3 20.10 − 320.10 − 3 Near (OU) (20 m) 4 pt 4 pt 4 pt 4 pt 4 pt 4 pt 4 pt 4 pt Time(hr) 12.5  12.5  6.5 11 10 10

Abbreviations: (C) indicates corrected vision, (m) indicates minutes,(hr) indicates hour, mm indicates millimeters, BD indicates baselinedistance vision; BN indicates baseline near vision, BP indicatesbaseline pupil size, OD indicates right eye; OS indicates left eye andOU indicates both eyes.

All percentages are w/v. “pt” reflects size of print materials, 4 beingequivalent to 20/20 vision and 3 to 20/15 vision.

“Time” refers to duration of the effect.

As seen in Table 2 aceclidine at a concentration of at least 1.1% w/vwas able to reduce the size of the pupil to 1.63 mm 1 hour after topicalinstillation resulting in corrected near and distance vision for atleast 10 hours. Lowering of the concentration of aceclidine to 0.75% w/v(formula #3) reduced the miotic effect to 2.0-2.5 mm after 1 hour andvision correction lasted only 6.5 hours. The addition of 0.03% w/vbrimonidine reduced redness of the eye (4 out of 4 without brimonidine,not shown) to 1.5 out of 4 within 30 minutes after topical instillationwhich was maintained for the entire time vision was corrected. Switchingthe nonionic surfactant to HPβCD (formulas #2-6) further reduced theredness of the eye. Lowering of the concentration of aceclidine to 0.75%w/v (formula #3) further reduced eye redness but as mention above alsoreduced the vision correction duration of the formula.

A brow ache and stinging in the eye were noticeable in formulas #1-3with a 2 out of 4 level of pain which was also associated with feelingsof slight nausea, upset stomach and fatigue. Surprisingly, the additionof a cycloplegic agent, tropicamide, reduced brow ache and stinging to0.5 out of 4 and 0 out of 4 respectively with brow ache dissipatingafter 60 minutes (formula # 4). Further, the raising of theconcentration of aceclidine to 1.1% w/v restored the longer duration ofcorrected vision seen in formulas #1-2 without increasing eye redness.However, upon re-topical instillation of formula #4 at the end of the 10hours noticeable brow ache occurred. Topical instillation of formula #5(OD) and (OS), with increased tropicamide concentrations, followingformula #4 relieved the brow ache experienced with re-installation offormula #4. Upon a 3^(rd) topical instillation, at the end of theeffective duration of formula #5, re-topical instillation of formula #5again led to considerable brow ache. Once again, in formula #6, raisingthe concentration of tropicamide was able to overcome the brow ache.Additionally and unexpectedly, tropicamide, despite being a cycloplegicagent, had no effect on pupil miosis or vision correction. Surprisingly,the addition of tropicamide resulted in a prolonged duration of optimalpupil size constriction.

To determine the effect of brimonidine on pupil miosis, formula #7, wasadministered. Administration of formula #7 resulted in only a slightdecrease in pupil miosis to 1.70 mm with identical distance and nearvision improvement to that of formula #5. A 2-3+ conjunctival injectionwas noted.

All baseline vision data was based on vision corrected with distancecontact lenses. Near vision was noted by subject as outstanding from 8inches to the horizon at 1.5 hours after installation. A MarcoAutorefractor with infrared camera and superimposed pupil calibrationscale was used for all pupil size measurements. Once an image wasselected it remained on screen allowing accurate calibration.

Example 3 Effect of Concentration of Aceclidine, Brimonidine,Guanfacine, Fadolmidine, Tropicamide and Additives

TABLE 3 Effect of concentration of aceclidine, brimonidine, guanfacine,fadolmidine, tropicamide and additives. AB2T AB4T AB6T AB11T AB12TPROPH13 Aceclidine 1.55 1.55 1.55 1.55 1.85 1.55 Brimonidine 0.037 0.0370.037 0.037 Fadolmidine 0.037 Guanfacine 0.037 HPBCD 5.5 5.5 5.5 5.5 5.55 Tropicamide 0.043 0.043 0.043 0.043 0.042 0.043 CMC* 0.075 0.075 0.0750.075 0.075 0.075 NaCl 0.025 0.025 0.025 0.025 0.025 0.025 BAK 0.01 0.010.01 0.01 0.01 0.01 Glycerin 0.1 0.1 0.1 Poloxamer 188 0.1 0.05 Polyoxyl40 0.05 stearate pH 6.5 7.5 7.5 7.5 7.0 7.5 nasal 0 0 0 0 0 0 congestionstinging initial 0.75 0 1.5 3.5 0 1.5 stinging, 3 min 0.5 0 0 wash out 00 redness initial 0 0 1 D/C 1 1 redness 15 min 0 0 0 D/C 0 0 whitening 00 0 D/C 1.5 1.5 pain 0 0 0 D/C 0 0 vision near 20.30 20.15 20.15 D/C20.15 20.15 vision distance 20.20 20.20 20.20 D/C 20.20 20.20 onset(min) 20 12 16 D/C 12 16 duration (hrs) 5.5 7.5 7.5 D/C 7.5 7.5 colorclear yellow yellow yellow yellow yellow OVERALL 2.5 3.9 3.8 0 4 3.9 *1%= 2,500 cps

All percentages are w/v. Scores for nasal congestion, stinging initial,stinging, 3 min, redness initial, redness 15 min, whitening, pain andoverall are out of 4.

“pt” reflects size of print materials, 4 being equivalent to 20/20vision and 3 to 20/15 vision.

Baseline vision was 20.20 both eyes for distance; 20.70 right eyeunaided for near; 20.80 left eye for near (best @16″).

D/C stands for discontinued after eye washing due to intolerablestinging.

Aceclidine at a concentration of 1.55% w/v was able to reduce the sizeof the pupil to about 1.63 mm 30 minutes after topical instillationresulting in corrected near and distance vision to 20.20 or better forat least 6 hours, with noticeable affect lasting about 7.5 hours as seenin Table 3. Lowering of the concentration of aceclidine to 1.25% w/v(not shown) resulted in useful near vision improvement to about20.25-20.30, but not as effective as at the higher dose range alkalinepH resulted in quicker onset, longer duration, and greater effect. Theaddition of 0.037% w/v brimonidine reduced redness of the eye (4 out of4 without brimonidine, not shown) to baseline within 15 minutes aftertopical instillation which was maintained for the about the entire timevision was corrected. Adding glycerin 0.10% w/v noticeably reducedstinging. Adding instead poloxamer 188 0.05% w/v and polyoxyl 40stearate 0.05% w/v however reduced initial stinging further but was moreviscous. The combination of glycerin 0.1% w/v, poloxamer 188 0.1% w/v ata pH of 6.5 was noticeably reduced in onset, duration, comfort andeffectiveness. AB11T did not include glycerin, poloxamer 188, orpolyoxyl 40 stearate, which resulted in substantial stinging anddiscontinuation of the experiment with eye flush irrigation immediatelyafter topical instillation. Substitution of guanfacine 0.037% w/v inAB12T for brimonidine resulted in minimal initial redness with prolongedredness reduction and some degree of whitening, and appeared to provideoverall the best cosmesis though requiring slightly higher aceclidineconcentration for optimal effect.

All baseline vision data was based on vision corrected with distancecontact lenses. Near vision was noted by subject as outstanding from 8to 10 inches to the horizon at 30 minutes after installation for AB4Tand AB6T.

AB4T and AB6T were repeated both monocularly and binocularly.Substantial improvement in depth perception, near point acuity to 3 pt(20.15), and near point distance (8″, 20.20) was noted when both eyeswere treated vs. monocular treatment. Monocular treatment resulted inworsening of vision with both eyes open versus testing only the treatedeye.

Example 4 Effect of Concentration Of Aceclidine, Brimonidine,Tropicamide, and Additives

TABLE 4 Effect of concentration of aceclidine, brimonidine, tropicamide,and additives. #8 #9 #10 #11 #12 #13 #14 Aceclidine  0.61%  1.61%  1.61% 1.61%  1.61%  1.53%  1.53% Tropicamide 0.042% 0.042% 0.042% 0.042%0.042% 0.044% 0.044% Brimonidine 0.042% 0.042% 0.042% 0.042% 0.042% CMC 0.75%  0.75%  0.80%  0.87%  0.75%  0.75%  0.75% NaCl  0.25%  0.25% 0.50%  0.50%  0.25%  0.50%  0.50% BAK  0.01%  0.01%  0.01%  0.01% 0.01%  0.01%  0.01% pH 7.00 7.00 7.00 7.00 8.00 7.00 7.00 phosphatebuffer 5 mM 5 mM 5 mM 6 mM 5 mM 5 mM borate buffer 5 mM Onset (min) 1515 15 15 15 15 15 Duration (min) 7 7 10-12 10-12 7 9 7 Pupil range (mm)1.5-1.7 1.5-1.7 1.5-1.7 1.5-1.7 1.5-1.7 1.8-2.0 1.8-2.0 Dimming 0-4 1.51.5 1.5 1.5 1.5 0.5 0.5 Sting 0-4 1 1 1 1 1 1 1 Ache 0-4 0.25 0.25 0.250.25 0.25 0.00 0.00 Redness 0-4 0.5 0.5 0.5 0.5 1.5 1.0 0.5 Other waterywatery sl thicker sl residue watery watery watery Overall 0-5 3.5 3.5 44 2.5 4.5 4.75 #15 #16 #17 #18 #19 #20 #21 Aceclidine  1.53%  1.53% 1.53%  1.53%  1.45%  1.65%  1.75% Tropicamide 0.044% 0.044% 0.044%0.044% 0.042% 0.044% 0.035% Brimonidine 0.042% 0.042% 0.042% 0.042%0.042% 0.042% CMC  0.80%  0.80%  0.80%  0.80%  0.75%  0.75%  0.75% NaCl 0.50%  0.75%  0.75%  1.00%  0.25%  0.25%  0.25% BAK  0.01%  0.01% 0.01%  0.01%  0.01%  0.01%  0.01% pH 7.00 7.00 8.00 7.00 7.00 7.00 8.00phosphate buffer 5 mM 5 mM 5 mM 5 mM 5 mM 5 mM 6 mM borate buffer Onset(min) 15 15 15 15 15 15 15 Duration (min) 10-12 9 9 7 7 7 7 Pupil range(mm) 1.8-2.0 1.8-2.0 1.8-2.0 1.8-2.0 1.8-2.1 1.8-2.1 1.8-2.2 Dimming 0-40.5 0.5 0.5 0.5 0.5 0.5 0.5 Sting 0-4 1 1 1 1 1 1 1 Ache 0-4 0.00 0.000.00 0.00 0.00 0.25 0.00 Redness 0-4 0.5 0.5 1.0 0.5 0.5 0.5 0.5 Othersl thicker sl thicker sl thicker thicker watery watery watery Overall0-5 5 5 5 4 4 4 4

As seen in Table 4, formulas #8-9, an increase in brimonidine to 0.42%w/v resulted in redness reduction to 0.5, while 0.75% w/v CMC resultedin a watery consistency. Unexpectedly, increasing CMC from 0.75% w/v toa range of 0.80% w/v to 0.87% w/v and increasing NaCl from 0.25% w/v to0.75% w/v in formulas #10-11 resulted in a thicker consistency and anincreased residence time from 7 hours to 10-12 hours and decreased theamount of drug that drained into the nasolacrimal duct. This decreaseddrug delivery to the nasal passages results in less nasal congestion.

In formulas #13-18 a decrease in the amount of aceclidine from 1.61% to1.53% w/v resulted in a pupil size range from 1.8-2.0 mm. Dimming as aresult of the restriction of the pupil decreased linearly from 1.5 to0.5 with the decreased amount of aceclidine. Specifically, the 1.8 to2.0 mm pupil created 41% more light than the 1.5 to 1.7 mm pupil.Surprisingly, the 1.8 to 2.0 mm pupil had a near depth increase of 1.75D. This is only a 0.25 D loss from the beneficial 2.00 D seen with the1.5-1.7 mm range. Thus, the 1.80 to 2.0 mm range produces 41% more lightwhile still allowing the full benefit of increased near vision inindividuals under 60 years of age; whereas, individuals 60 years of ageand over still experience total computer benefit and some increased nearbenefit.

The increase in tropicamide concentration from 0.042% w/v (formulas#8-#11) to 0.044% w/v (formulas #13-#18) resulted in a decrease in acheto negligible amounts. The amount of ache may also be correlated withthe age of the individual. For those individuals under the age of 45, anincrease of tropicamide concentration to a range from 0.046% to 0.060%w/v may be preferred.

Further, Table 4 shows an unexpected result seen in formulas #13 and #17where the increase of NaCl from 0.25% w/v to a range of 0.50 to 0.75%w/v resulted in an acceptable redness score of only 1.0 even without theaddition of the redness reducing agent brimonidine.

Formulas #15, #16 and #17 each result in an overall maximum rating of 5by combining the benefits of: (1) reduced aceclidine concentrations toimprove the amount of light produced without significantly affecting thenear vision benefits seen in formulas #8-#12; (2) increased NaClconcentrations resulting in a further reduction in redness even in theabsence of brimonidine; and (3) increased CMC concentrations resultingin longer residency time on the eye.

Formula #19 is an excellent alternative for the minority of individualsthat are high responders to formulas #15-#17 and get noticeable dimmingwith 1.53% w/v aceclidine. Formula #20 is an excellent alternative forthe minority of individuals that are low responders to formula #19.Lastly, Formula #21 is an excellent alternative for the minority ofindividuals that are low responders and get poor pupil response withFormula #20.

Example 5 Comparison of Effects of Polyoxyl 40 Stearate, HPβCD andPoloxamer 407

TABLE 5 Comparison of Effects of Polyoxyl 40 Stearate, HPβCD andPoloxamer 407. #22 #23 #24 Aceclidine  1.45%  1.45%  1.45% Tropicamide0.044% 0.044% 0.044% Brimonidine 0.040% 0.040% 0.040% Polyoxyl 40Stearate  5.5% HPβCD  5.5% Poloxamer 407  5.5% CMC  0.80%  0.80%  0.80%NaCl 0.037% 0.037% 0.037% EDTA 0.015% 0.015% 0.015% BAK 0.007% 0.007%0.007% pH 7.00 7.00 7.00 phosphate buffer 5 mM 5 mM 5 mM NasalCongestion 0.00 0.50 1.50 Stinging 0.25 0.25 0.25 Wetting 4.00 4.00 4.00Redness 0.25 0.50 0.50 Visual Blur (<15 sec) 0.50 0.50 1.50 Duration 6-8hrs 6-8 hrs 6-8 hrs Overall 0-4 4.00 4.00 4.00

Clinical Protocol

20 presbyopic patients with full distance correction were each given oneof the above formulas (#22-#23). All patients received pre- andpost-drop distance and near acuity measurement, Zeiss Visante® (Visanteis a registered trademark of Carl Zeiss Meditec AG) optical adherencetomography, axial length and contrast acuity testing (i.e.Colenbrander-Michelson 10% Lum target) with the following results:

-   all patient achieved a miotic pupil of 1.5 to 2.20 mm;-   no patient experienced ciliary ache, ciliary spasm, or induced    accommodation;-   all patients achieved 20/30+ visual acuity or better at 14″ and were    very satisfied with their high contrast near vision results and    there was no significant complaint of burning or aching;-   the duration of effect lasted 6 -8 hrs in all cases;-   binocular vision afforded all patients 1-1.5 additional lines of    near acuity over monocular testing;-   the last 10 patients were tested at 20″ (i.e. computer distance,    cell phone distance) and all achieved 20/25 or better near visual    acuity;-   moderately hyperopic (approx. +2.25 sphere) uncorrected presbyopes    were very satisfied with distance visual acuity that improved to a    20/25 or better level at distance and near vision in the 20/30    range; and-   uncorrected distance acuity was often improved for those patients    who chose not to routinely correct a small refractive error.

As seen in Table 5, the use of polyoxyl 40 stearate provides the mostcomfortable aceclidine formulation with the least amount of visual blurand redness. To achieve similar results to that of formula #22, formula#23 requires 10-15% higher concentrations of the non-ionic surfactantand formula #24 requires 15-20% higher concentrations of the non-ionicsurfactant. HPβCD induced a color change over time, possibly indicativeof oxidation. Captisol® (sulfobutylether β-cyclodextrin) was substitutedwith similar findings.

Example 6 Modulation of Aceclidine Concentrations in a PreferredEmbodiment

Preferred embodiment:

-   Aceclidine 1.35%-1.55% w/v;-   Polyoxyl 40 stearate 5.5% w/v;-   NaCl 0.037% w/v;-   a viscosity agent, preferably CMC 0.80% w/v or an amount of Carbopol    934 or 940 sufficient to achieve a viscosity of from about 5 to    about 35 cps upon topical instillation, such as Carbopol® 940 at a    concentration from about 0.09% to about 1.0% w/v;-   BAK 0.015% w/v; and-   optionally, a phosphate, citrate, citrophosphate, or acetate buffer    from about 3 to about 10 mM, wherein the pH is from about 4.75 to    about 6.0.

For 1.35% w/v aceclidine

Stinging on topical instillation 0.25/4.0 (lasting about 2-5 seconds);

Induced redness at 10 minutes: 1.0 to 1.5/4.0;

Induced redness at 30 minutes: 0.0 to 0.25/4.0;

Comfort: very high.

Wetting: very high, the eye maintaining sensation of improved wettingfor most of a 24 hour period after a single topical instillation.

Depth of Focus distance: excellent.

Depth of Focus near: excellent.

In testing the above formulations on several subjects it was discoveredthat there is a slight range in clinical effect depending on theconcentration of aceclidine, where 1.35%-1.55% w/v aceclidine ispreferred, but for which 1.35% w/v and 1.45% w/v confer the desiredbenefits on most subjects.

Further, it is discovered that the clinical effect of 1.35% w/vaceclidine can be improved when instilled as follows:

-   1) baseline effect: 1 drop to each eye.-   2) enhanced effect: 2 drops to each eye.-   3) greater effect: after 2) above repeat 1) above.-   4) maximum effect: after 2) above repeat 2) above.

Example 7 Use of a Preferred Embodiment to Prolong Contact Lens Wear

Preferred embodiment:

-   Aceclidine 1.45% w/v;-   Polyoxyl 40 stearate 5.5% w/v;-   NaCl 0.037% w/v;-   a viscosity agent, preferably CMC 0.80% w/v or an amount of    Carbopol® 934 or 940 sufficient to achieve a viscosity of from about    5 to about 35 cps upon topical instillation, such as Carbopol® 940    at a concentration from about 0.09% to about 1.0% w/v;-   BAK 0.02% w/v; and-   optionally, a phosphate, citrate, citrophosphate, or acetate buffer    from about 3 to about 10 mM, wherein the pH is from about 4.75 to    about 6.0.

As a baseline, the subject, who normally wore extended wear lenses (AirOptix®; Air Optix is a registered trademark of Novartis AG) for dailywear only, slept in these lenses overnight. On arising each morning thesubject's vision was blurred and the contact lenses required removal andcleaning of film and deposits that had formed overnight. Average visionon arising at distance: 20.60; average vision at near on a Michelsoncontrast acuity chart: 20.80.

Then, for seven consecutive days the above formulation was instilledbetween 7 am and 10 am each day as a single dose. Subject wore the AirOptix® lenses throughout each day and slept in the lenses overnight.Upon arising each morning the subject's vision at distance: 20.20+;vision at near 20.40 unaided (consistent with subject's baselinepresbyopia when the subject did not wear the lenses overnight andinstead inserted the lenses upon arising).

Example 8 Comparison of Effects of Polyoxyl 40 Stearate and Captisol®(Sulfobutylether β-cyclodextrin

TABLE 6 Comparison of Effects of Polyoxyl 40 Stearate and Captisol ®(sulfobutylether β-cyclodextrin). #25 #26 #27 #28 #29 #30 #31 #32 #33Aceclidine 1.35% 1.35% 1.35% 1.35% 1.35% 1.35% 1.35% 1.35%  1.35%Tropicamide 0.044% 0.044% 0.044% 0.044% 0.044% 0.044% 0.044% 0.044%0.044% Polyoxyl 40 stearate 5.5% 5.5% 5.5% 5.5% 5.5% 5.5% 5.5%Captisol ® 5.5%  5.5% Cocamideopropyl betaine 0.10% EDTA 0.015% 0.015%0.005% 0.005% 0.005% 0.005% 0.015% CMC 1% = 2,500 cps 0.80% 0.80% 0.80%0.80% 0.80% 0.80% 0.80% 0.80%  0.80% NaCl 0.037% 0.037% 0.037% 0.037%0.037% 0.037% 0.037% 0.037% 0.037% Mannitol 4%    4% BAK 0.007% 0.007%0.007% 0.007% 0.007% 0.007% 0.007% 0.007% 0.007% Borate buffer (mM) 4 44 4 4 4 4 Phosphate buffer (mM) 4 4 pH 7 7 7 7 7 7 7 7 7 Redness, 10 min1.25 1.25 2 2 1.75 1.75 0 0 0 Redness, 30 min 0 0 1.5 1.5 1.25 1.25 0 00 Pupil, 30 min (mm) <2 <2 <2 <2 <2 <2 <2 <2 <3 Blur on instill (sec) 1010 10 10 10 10 10 10 10 Ache 0 0 0 0 0 0 1 0 0 Rating 4.00 4.00 2.002.00 2.50 2.50 1.00 5.00 TBD

As seen in Table 6, when using polyoxyl 40 stearate as the surfactantthe exclusion of EDTA results in reduced redness and best overall ratingamong polyoxyl 40 stearate compositions (Formulas #25 and #26). Theaddition of cocamidopropyl betaine (“CAPB”) further reduces rednesshowever results in significant ache (Formula #31). Replacing polyoxyl 40stearate with Captisol® (sulfobutylether β-cyclodextrin) and addingmannitol achieves similar results in redness reduction as the additionof CAPB to polyoxyl 40 stearate but without the attendant ache resultingin the highest overall rating among aceclidine compositions (Formula#32). After several weeks formulations with Captisol® (sulfobutyletherβ-cyclodextrin) had an orange hue, possibly indicative of oxidation.

Example 9 Preferred Cold Chain Composition

Composition

-   aceclidine at a concentration of about 1.40%-1.80% w/v; and-   tropicamide at about 0.42% w/v;-   polyoxyl 40 stearate at about 5.5% w/v;-   mannitol at a concentration of about 2.5% to 4.5% w/v;-   carbomer 940 at a concentration of about 0.09% to about 2.0% w/v;-   optionally, a preservative such as BAK at a concentration of about    0.2% w/v;-   optionally citrate at a concentration of about 0.1%;-   optionally with acetate or phosphate buffer at 2-100 mM, more    preferably 3-5 mM-   wherein said composition has a pH of about 4.50 to about 5.0; and    preferably, about 4.75 to about 5.0; and-   wherein w/v denotes weight by volume

A composition as described above was administered to a 62 year oldsubject. It resulted in pupils of 1.8-1.9 mm ou, 20.20+ reading vision,and 20.20+ distance vision; whereas without carbomer 940 reducedeffectiveness resulted at 2.5% mannitol, and no near vision effectresulted at 4.0% mannitol. No ciliary spasm or loss of distance visionresulted. Onset was within about 15 minutes. Transient redness of about1+/out of 4 was noted for about 20 minutes without alpha agonistvasoconstrictor. The presence or absence of BAK had no clinical effect,and was used to provide an optional preservative.

Example 10 Stabile Aceclidine Formulations Composition Tested:

-   aceclidine at a concentration of about 1.50% w/v;-   tropicamide at a concentration of about 0.042% w/v;-   polyoxyl 40 stearate at a concentration of about 5.5% w/v;-   mannitol at a concentration of about 2.5% w/v;-   citrate at a concentration of about 3 mM;-   wherein said composition has a pH of about 4.75.

20 samples of the above composition were divided evenly and stored at25° C. and 4° C. Prior to storage, initial concentrations of aceclidinewere measured using high-pass liquid chromatography (“HPLC”). The amountof aceclidine in each solution was calculated by the area under theprincipal peak compared to a reference solution of aceclidine. Sampleswere then subject to storage for 3 months. Aceclidine measurements weretaken at 1, 2 and 3 months. Results of the stability test are shown inTable 7.

TABLE 7 Stability of Aceclidine in Cold Chain Storage 25° C. 4° C.Initial 100% 100% 1 month  92%  93% 2 months  75%  92% 3 months  50% 88%

As seen in Table 7 “cold chain storage” or storage of the aceclidinecomposition at from 2° C. to 8° C. resulted in a significant increase instability of aceclidine at all 3 time points.

Example 11 Use of Compositions Containing Little or No Cycloplegic Agent

Aceclidine alone causes incidence migraine-like severe ciliary spasm(brow ache) and myopic blur. These effects are inversely correlated toage with subjects age 40 reporting the highest incidence and subject age60+ reporting the lowest incidence. The addition of a cycloplegic agentreduces ciliary spasms and attendant brow ache, migranious headache,squeezing pressure around eyes or other symptoms of ciliary spasms. Theaddition of the cycloplegic agent, surprisingly, does not reduce themyopic effect of aceclidine. The addition of 2.5% w/v mannitol howeverdoes reduce the myopic effect of aceclidine. Increasing the aceclidineconcentration overcomes this reduction in myopic effect seen with theaddition of mannitol. Surprisingly, however, the increase in aceclidineis not coincident with an increase in ciliary spasm. Even moresurprising, the concentration of the cycloplegic agent can be reduced oreven eliminated in the presence of mannitol without an increase inciliary spasm. Thus, combining a higher concentration of aceclidine withlittle to no cycloplegic agent in the presence of mannitol results in animprovement of near vision acuity without attendant side effects on parwith lower concentrations of aceclidine and higher concentrations of thecycloplegic agent in the absence of a cycloplegic agent.

Further and unexpectedly, the addition of a nonionic surfactantincreases both the quantitative measure of near vision improvement andthe duration. This effect is concentration sensitive. In a preferredembodiment the non-ionic surfactant is at least 1%, preferably at least2%, more preferably from about 1% to about 5%, and most preferably about5%. For example, polysorbate 80 or polyoxyl 40 stearate at aconcentration from about 1% to about 5% w/v results in about 1.5 toabout 2.0 lines of improvement and a duration from about 4 to about 5hours.

Not to be held to particular theory, the increase in concentration of asurfactant may crowd the surface of the cornea, and at an optimalconcentration this crowding result in small and probably nanometerdiameters, which given the dual polarity of surfactants, where nonionicare most preferred, enhances corneal absorption of the entrapped highlypolar aceclidine molecules.

The further addition of a viscosity agent by itself does not enhanceduration. Surprisingly, the addition of a viscosity agent in aformulation with optimal ratios of aceclidine, tropicamide and anon-ionic surfactant dramatically improves duration. For example, aformulation of the present invention comprising 1.75% aceclidine, 2.5%mannitol, 0.01% tropicamide, 5% polysorbate 80 improves near vision in apresbyopic patient by up to 3 lines of vision acuity for about 4 toabout 5 hours. The addition of 1.4% CMC further increases the nearvision improvement to from about 7 to about 10 hours. Not to be held toa particular theory, a threshold above the critical micellar thresholdgreatly enhances permeation through the cornea by reducing micelle sizefrom micrometers to nanometers. See FIG. 2.

Examples of compositions containing little or no cycloplegic agent areshown in Table 8 below.

TABLE 8 Compositions containing little or no cycloplegic agent #L1 #L2#L3 #L4 #L5 #L6 Aceclidine 1.75% 1.75% 1.75% 1.75% 1.75% 1.75%Tropicamide 0.02% 0.02% 0.02% 0.02% 0.02% — Mannitol  2.5%  2.5%  2.5% 2.5%  2.5%  2.5% Polysorbate 80 0.75% 0.25% 0.25%  0.1%  0.1% 0.5%^(#)Carbopol ® 940 0.95% 0.95% 0.95%  0.9% 0.95% 0.95%* or CMC GlycerinePhosphate buffer 3 mM — 3 mM 3 mM 3 mM 3 mM NaCl  0.5%  0.1% 0.05% — 0.1% 0.5%^(#) Boric acid — 0.12%  0.2%  0.2% 0.12% — BAK 0.015%  0.01%0.01% 0.05% 0.01% 0.015%  pH 5.0 5.0 5.0 5.0 5.0 5.0 #L7 #L8 #L9 #L10#L11 #L12 Aceclidine 1.75% 1.75% 1.75% 1.75% 1.65% 1.65% Tropicamide — —— — 0.01% — Mannitol  2.5%  2.5%  2.5%  2.5%  2.5%  2.5% Polysorbate 800.25% 0.25%  0.1%  0.1%   2%   2% Carbopol ® 940  0.95%*  0.95%*  0.9%*0.95%* 0.75% 0.75% or CMC Glycerine 0.10% 0.10% Phosphate buffer — 3 mM3 mM 3 mM 3 mM 3 mM NaCl  0.1% 0.05% —  0.1% — — Boric acid 0.12%  0.2% 0.2% 0.12% — — BAK 0.01% 0.01% 0.05% 0.01% 0.01% 0.01% pH 5.0 5.0 5.05.0 5.0 5.0 #L13 #L14 #L15 #L16 #L17 #L18 Aceclidine 1.75%  1.75%  1.65% 1.75%  1.75%  1.75% Tropicamide — 0.025% 0.025% 0.025% 0.025% 0.025%Mannitol  2.5%  2.5%  2.5%  2.5%  2.5%  2.5% Polysorbate 80   1%  0.10% 2.50%  2.50%  3.00%  2.50% Carbopol ® 940 0.75%  0.75%  0.75%  0.75% 0.75%  1.50% or CMC Glycerine 0.10%  0.10%  0.10%  0.10%  0.10%  0.10%Phosphate buffer 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM NaCl — — — — — — Boricacid — — — — — — BAK 0.01%  0.01% 0.015% 0.015% 0.015% 0.015% pH 5.0 5.05.25 5.25 5.25 5.25 #L19 #L20 #L21 Aceclidine  1.75%  1.75%  1.75%Tropicamide 0.025% 0.015% 0.015% Mannitol  2.5%  2.5%  2.5% Polysorbate80  2.50%  2.50%  2.50% Carbopol ® 940  0.75%  0.75%  0.75% or CMCGlycerine  0.20%  0.20%  0.20% Phosphate buffer 3 mM 3 mM 3 mM NaCl — —— Boric acid — — — BAK 0.015% 0.015% 0.015% pH 5.25 5.25 5.25 #L22 #L23#L24 #L25 #L26 #L27 Aceclidine  1.65%  1.75%  1.75%  1.75%  1.75%  1.65%Tropicamide 0.025% 0.275% 0.020% 0.015% 0.027% 0.0275%  Mannitol  2.5% 2.5%  2.5%  2.5%  2.5%  2.5% Polysorbate 80    5%    5%    5%    5%   5%    5% Carbopol ® 940  1.25%  1.45%  1.45%  1.45%  1.45%  1.25% orCMC Glycerine Phosphate buffer 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM NaCl — — —— — — Boric acid — — — — — — BAK  0.01%  0.01%  0.01%  0.01%  0.01% 0.01% pH 5.0 5.0 5.0 5.0 6.0 5.0 Pupil Size (mm) Reading vs.  3+   3+  3+   3+   3+   3+  Baseline 40 cm Duration (hours) 7    10+   10+  10+   10+  7.0 Ciliary Spasms 0.0 tr 0.5 1.0 1.0 0.0 Stinging 0.5 0.50.5 0.5 0.5 0.5 Blur (min) 1   1   1   1   1   1   Distance Blur Onset(min) 20   20   20   20   20   20   Redness 1 hr (0-4) 0.5 0.5 0.5 0.50.5 0.5 Redness 4 hr (0-4) Overall Comfort sl sticky sl sticky sl stickysl sticky sl sticky sl sticky Osmolarity Efficacy index: read*durOVERALL (1-5) best best best best best best #L28 #L29 #L30 #L31 #L32Aceclidine  1.75%  1.75%  1.75%  1.75%  1.75% Tropicamide 0.0275% 0.0275%  0.025% 0.022% 0.0175%  Mannitol  2.5%  2.5%  2.5%  2.5%  2.5%Polysorbate 80    5%    5%    5%    5%    5% Carbopol ® 940  1.40% 1.40%  1.50%  1.40%  1.50% or CMC Glycerine Phosphate buffer 3 mM 3 mM3 mM 3 mM 3 mM NaCl — — — — — Boric acid — — — — — BAK  0.01%  0.01% 0.01%  0.01%  0.01% pH 5.0 5.0 5.0 5.0 6.0 Pupil Size (mm) Reading vs. 3+   3+   3+  Baseline 40 cm Duration (hours)  10+   10+   10+  CiliarySpasms tr 0.5 1.0 1.0 Stinging 0.5 0.5 0.5 Blur (min) 1   1   1  Distance Blur Onset (min) 20   20   20   Redness 1 hr (0-4) 0.5 0.5 0.5Redness 4 hr (0-4) Overall Comfort sl sticky sl sticky sl stickyOsmolarity Efficacy index: read*dur OVERALL (1-5) best best best #L33#L34 #L35 #L36 #L37 #L38 Aceclidine 1.75% 1.40% 1.40% 1.25% 1.45% 1.45%Tropicamide — — — — — 0.0200%  Brimonidine — — — — — — Mannitol — — — —— — Polysorbate 80 — — — — — — Polyoxyl 40 — — — —  5.5%  5.5% StearateCitrate 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% Glycerine — 0.10% 0.10%0.10% 0.10% 0.10% CMC — 1.45% 0.75% — 0.85% 0.75% HPMC — — — — — —Carbopol ® 940 — — — — — — NaCl 0.75% 0.75% 0.50% 0.50% 0.50% 0.50%Boric Acid — — — — — — Postassium Borate — — — — — — Phosphate buffer 33 3 3 3 3 Acetate — — — — — — pH 5.0 5.0 5.0 5.0 5.0 5.0 BAK 0.015% 0.015%  0.015%  0.015%  0.015%  0.015%  Pupil Size (mm) Reading vs. 33.25 3 2 3 2.5 Baseline 40 cm Duration (hours) 4 7 4.5 6.5 6 CiliarySpasms 4 4 3 2 3 2 Stinging 1.0 1.0 1.0 1.0 Blur (min) Distance blurnone none none none none none Onset (min) 20-11 20-12 20-13 20-14 20-1520-16 Redness 1 hr (0-4) 2.0 1.5 0.5 0.5 Redness 4 hr (0-4) Overallcomfort poor poor poor fair poor poor Osmolarity hi hi hi hi hi hiEfficacy index: 12 23 14 0 20 15 read*dur OVERALL (1-5) * ** ½ * — * **#L47 #L48 #L49 #L50 #L51 #L52 Aceclidine 1.45% 1.55% 1.65% 1.75% 1.65%1.65% Tropicamide — 0.0200%  0.0300%  0.0300%  0.0200%  0.0100% Brimonidine — — — — — — Mannitol  2.5%  4.0%  2.5%  2.5%  2.5%  2.5%Polysorbate 80 — — — 5.00% — 2.00% Polyoxyl 40  5.5%  5.5%  5.5% —  5.5%— Stearate Citrate 0.10% 0.10% 0.10% — 0.10% — Glycerine 0.10% 0.10%0.10% 0.10% 0.10% 0.10% CMC 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% HPMC — —— — — — Carbopol ® 940 — — — — — — NaCl 0.50% 0.50% 0.50% 0.50% 0.00%0.50% Boric Acid — — — — — — Postassium Borate — — — — — — Phosphatebuffer 3 3 3 3 3 3 Acetate — — — — — — pH 5.0 5.0 5.25 5.0 5.0 5.0 BAK0.015%  0.015%  0.015%  0.015%  0.015%  0.015%  Pupil Size (mm) Readingvs. 1.5 0.5 1.5 1.5 1 2.5 Baseline 40 cm Duration (hours) 3 2 4 4 2 6Ciliary Spasms 0.5 0.5 0.5 0.5 0.5 0.5 Stinging 1 1 0.5 1 1 1 Blur (min)Distance blur none none none none none none Onset (min) 20-25 20-2520-25 20-25 20-25 20-25 Redness 1 hr (0-4) 0.5 0.5 0.5 0.5 0.5 0.5Redness 4 hr (0-4) Overall comfort good good good good good poorOsmolarity hi hi hi hi hi hi Efficacy index: 5 1 6 6 2 15 read*durOVERALL (1-5) *** * * * * ** #L53 #L54 #L55 #L56 #L57 #L58 Aceclidine1.65% 1.65% 1.75% 1.75% 1.65% 1.65% Tropicamide 0.0250%  0.0000% 0.0000%  0.0250%  0.0250%  0.0250%  Brimonidine — — — — — — Mannitol 2.5%  2.5%  2.5%  2.5%  2.5%  2.5% Polysorbate 80 2.50% 2.00% 1.00%0.10% 2.00% 2.50% Polyoxyl 40 — — — — — — Stearate Citrate 0.10% — — — —— Glycerine 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% CMC 0.85% 0.85% 0.85%0.85% 0.85% 0.85% HPMC — — — — — — Carbopol ® 940 — — — — — — NaCl 0.50%— — — — — Boric Acid — — — — — — Postassium Borate — — — — — — Phosphatebuffer 3 3 3 3 3 3 Acetate — — — — — — pH 5.0 5.0 5.3 5.3 5.3 5.00 BAK0.015%  0.015%  0.015%  0.015%  0.015%  0.015%  Pupil Size (mm) Readingvs. 3 3 2 1.5 2.5 3 Baseline 40 cm Duration (hours) 5 6 4 4 6 5.5Ciliary Spasms 0.5 2 2 0 0 0 Stinging 0.5 1 0.5 0.5 0.5 0.5 Blur (min)Distance blur none none none none none none Onset (min) 20-25 20-2520-25 20-25 20-25 20-25 Redness 1 hr (0-4) 0.5 0.5 0.5 1.0 0.5 0.5Redness 4 hr (0-4) Overall comfort poor poor poor good good goodOsmolarity hi nl nl nl nl nl Efficacy index: 15 18 8 6 15 17 read*durOVERALL (1-5) #L59 #L60 #L61 #L62 #L63 #L64 Aceclidine 1.65% 1.65% 1.65%1.75% 1.65% 1.75% Tropicamide 0.0150%  0.0400%  0.0250%  0.0300% 0.0250%  0.0250%  Brimonidine — — — — — — Mannitol  2.5%  2.5%  2.5% 2.5%  2.5%  2.5% Polysorbate 80 2.50% 3.50% 2.50% 3.50% 2.50% 3.50%Polyoxyl 40 — — — — — — Stearate Citrate — — — — — — Glycerine 0.10%0.10% 0.10% 0.10% 0.10% 0.10% CMC 0.75% 0.60% 1.60% 0.60% 0.75% 0.50%HPMC — — — — — — Carbopol ® 940 0.75% 0.60% 0.60% 0.50% NaCl — — — — — —Boric Acid — — — — — — Postassium Borate — — — — — — Phosphate buffer 33 3 3 3 3 Acetate — — — — pH 5.00 5.00 5.00 5.00 5.00 5.00 BAK 0.015% 0.015%  0.015%  0.015%  0.015%  0.015%  Pupil Size (mm) Reading vs. 21.5 2.5 2.5 2 2.5 Baseline 40 cm Duration (hours) 7 3 7 7 4 CiliarySpasms 0.5 0 0.5 0.5 0.5 0.5 Stinging 0.5 0.25 0.25 0.25 0.5 0.5 Blur(min) 1.5 1 2 Distance blur none none none none none none Onset (min)20-25 20-25 20-25 20-25 20-25 20-25 Redness 1 hr (0-4) 0.5 0.5 0.5 0.50.5 Redness 4 hr (0-4) Overall comfort good good good good good goodOsmolarity nl nl nl nl nl nl Efficacy index: 14 5 18 18 8 0 read*durOVERALL (1-5) **** **** poor #L65 #L66 #L67 #L68 #L69 #L70 Aceclidine1.65% 1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide 0.0250%  0.0275% 0.0275%  0.0275%  0.0250%  0.0180%  Brimonidine — — — — — — Mannitol 2.5%  2.5%  2.5%  2.5%  2.5%  2.5% Polysorbate 80 4.00% 5.00% 5.00%2.00% 2.00% 2.00% Polyoxyl 40 — — — — — — Stearate Citrate — — — — — —Glycerine 0.10% — — — — — CMC 0.75% — 1.35% 1.35% 1.45% HPMC — — — — — —Carbopol ® 940 1.35% — 1.45% — — NaCl — — — — — — Boric Acid — — — — — —Postassium Borate — — — — — — Phosphate buffer 3 3 3 3 3 3 Acetate — — —— — pH 5.00 5.0 5.0 5.0 5.0 5.0 BAK 0.015%  0.015%  0.015%  0.015% 0.015%  0.015%  Pupil Size (mm) Reading vs. 2 2.75 2.75 2.75 2.75 2.75Baseline 40 cm Duration (hours) 5 7 7 5.5 6 7 Ciliary Spasms 0.5 0.5 0.50.5 0.5 0.5 Stinging 0.5 0.5 0.5 0.5 Blur (min) Distance blur none nonenone none none none Onset (min) 20-25 20-25 20-25 20-25 20-25 20-25Redness 1 hr (0-4) 0.5 0.5 0.5 0.5 Redness 4 hr (0-4) Overall comfortgood good good good good good Osmolarity nl nl nl nl nl nl Efficacyindex: 10 19 19 15 17 19 read*dur OVERALL (1-5) ? ** ½ ** #L71 #L72 #L73#L74 #L75 #L76 Aceclidine 1.75% 1.75% 1.75% 1.75% 1.75% 1.75%Tropicamide 0.0160%  0.0160%  0.0150%  0.0150%  0.0150%  0.0120% Brimonidine — — — — — — Mannitol  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%Polysorbate 80 2.25% 4.00% 4.00% 5.00% 5.00% 5.00% Polyoxyl 40 — — — — —— Stearate Citrate — — — — — — Glycerine — — — — — — CMC 1.45% 1.45%1.45% 1.45% 1.43% 1.43% HPMC — — — — — — Carbopol ® 940 — — — — NaCl — —— — — — Boric Acid — — — — — — Postassium Borate — — — — — — Phosphatebuffer 3 3 3 3 3 3 Acetate — — — — — — pH 5.0 5.0 5.0 5.0 5.0 5.0 BAK0.01% 0.01% 0.01% 0.01% 0.01% 0.01% Pupil Size (mm) Reading vs. 2.752.75 3 3.25 3.25 3.5 Baseline 40 cm Duration (hours) 7 7 7.5 7.5 7.5 7Ciliary Spasms 0.5 0.5 0.5 0.5 0.5 1 Stinging Blur (min) 1 1.5 1.5 1.5Distance blur none none none none none none Onset (min) 20-25 20-2520-25 20-25 20-25 20-25 Redness 1 hr (0-4) Redness 4 hr (0-4) Overallcomfort good good good good-exc good-exc good-exc Osmolarity nl nl nl nlnl nl Efficacy index: 19 19 23 24 24 25 read*dur OVERALL (1-5) **** ****½ ***** ***** *****! #L77 #L78 #L79 #L80 #L81 #L82 Aceclidine 1.75%1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide 0.0110%  0.0100%  0.0000%  —0.0100%  0.0150%  Brimonidine — — 0.015%  — — — Mannitol  2.5%  2.5% 2.5%  2.5%  2.5%  2.5% Polysorbate 80 5.00% 5.00% 5.00% — 6.00% 7.00%Polyoxyl 40 — — — — — — Stearate Citrate — — — — — — Glycerine — — — — —— CMC 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% HPMC — — — — — — Carbopol ®940 — — — — — — NaCl — — — — — 0.50% Boric Acid — — — — — — PostassiumBorate — — — — — — Phosphate buffer 3 3 3 3 3 3 Acetate — — — — — — pH5.0 5.0 5.0 5.0 5.0 BAK 0.01% 0.01% 0.01% — 0.01% 0.01% Pupil Size (mm)Reading vs. 3.5 3.75 2.5 2.5 2.75 2.5 Baseline 40 cm Duration (hours) 89 8 7 5.5 5 Ciliary Spasms 1 1 2 2 0.5 0.5 Stinging Blur (min) Distanceblur none none none none none none Onset (min) 20-25 20-25 20-25 20-2520-25 20-25 Redness 1 hr (0-4) Redness 4 hr (0-4) Overall comfort excexc fair fair good good Osmolarity nl nl nl nl nl hi Efficacy index: 2834 20 18 15 13 read*dur OVERALL (1-5) *****!! *****!! **** **** *** ***#L83 #L84 #L85 #L86 #L87 #L88 Aceclidine 1.65% 1.40% 1.75% 1.75% 1.75%1.75% Tropicamide 0.0000%  0.0000%  0.0000%  0.0100%  0.0900%  0.0060% Brimonidine — — — — — — Mannitol  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%Polysorbate 80 0.00% 0.00% 5.00% 2.5% 2.5% 2.5% Polyoxyl 40 —  5.5% — —— — Stearate Citrate — — — — — — Glycerine — — — — — — CMC 0.00% 0.75%1.40% — — — HPMC — — — 1.75% 1.75% 1.75% Carbopol ® 940 — — — — — — NaCl— — 0.00% 0.50% — 0.50% Boric Acid — — — — 0.35% — Postassium Borate — —— — 0.47% — Phosphate buffer 3 3 3 3 3 3 Acetate — — — — — — pH 5.0 5.05.0 5.0 5.0 5.0 BAK 0.010%  0.010%  0.010%  0.020%  0.020%  0.020% Pupil Size (mm) Reading vs. 1 1.5 3.5 3.5 3.5 3.75 Baseline 40 cmDuration (hours) 3 3.5 7 8 7 9 Ciliary Spasms 1 1 2 0.5 0.5 0.5 Stinging1.0 0.5 Blur (min) Distance blur none none 2.0 none none none Onset(min) 20-25 20-25 20-25 20-25 20-25 20-25 Redness 1 hr (0-4) 2.0 1.0 1.00.5 0.5 Redness 4 hr (0-4) Overall comfort fair good good good goodOsmolarity nl nl nl nl nl nl Efficacy index: 3 5 25 28 25 34 read*durOVERALL (1-5) * **** #L89 #L90 #L91 #L92 #L93 #L94 Aceclidine 1.75%1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide 0.0060%  0.0100%  0.0060% 0.0060%  0.0060%  0.0060%  Brimonidine — — — — — — Mannitol  2.5%  2.5% 2.5%  2.5% —  2.5% Polysorbate 80 2.5% 2.50% 2.50% 2.75% 2.75% 3.50%Polyoxyl 40 — — — — — — Stearate Citrate — — — — — Glycerine — — — — — —CMC — — — — — — HPMC 1.75% — — — — — Carbopol ® 940 — 1.75% 1.75% 1.80%1.80% 1.80% NaCl — 0.50% 0.50% 0.50% 0.50% 0.50% Boric Acid — — — —0.25% — Postassium Borate — — — — 0.37% — Phosphate buffer 4 3 3 3 3 3Acetate — — — pH 6.0 5.0 5.0 5.0 5.0 5.0 BAK 0.020%  0.02% 0.02% 0.02%0.02% 0.02% Pupil Size (mm) Reading vs. 3.75 3.5 3.75 3.75 3.75 3.75Baseline 40 cm Duration (hours) 9 7 7 8 8 8.5 Ciliary Spasms 0.5 0.5 0.50 0 0 Stinging Blur (min) Distance blur none none none none none noneOnset (min) 20-25 20-25 20-25 20-25 20-25 20-25 Redness 1 hr (0-4) 0.50.5 0.5 0.5 0.5 0.5 Redness 4 hr (0-4) Overall comfort good Osmolaritylo Efficacy index: 34 25 26 30 30 32 read*dur OVERALL (1-5) ***** ********** ***** ***** All concentration in weight by volume. mm denotesmillimeters. cm denotes centimeters. min denotes minutes. %* denotesamount can optionally vary from about 0.01% to about 1% w/v. ^(#)denotesformulation can include polysorbate 80 or not include polysorbate 80.Ciliary spasms scores correspond to the following: 0 = no discomfort;0.5 = slight sting; 1 = noticeable squeeze/discomfort; 2 = pain for lessthan 30 minutes; 3 = pain for 1 hour or more; and 4 = severe tointolerable pain.

The efficacy index is demonstrated in FIG. 3. In brief, the score iscalculated by multiplying the lines of improvement in near visual acuityby the number of hours the improvement lasts. For example a score of: 5is equal to +1 lines of improvement in near visual acuity for 5 hours;10 is equal to +1.5 lines of improvement for 6.7 hours; 15 is equal to 2lines of improvement for 7.5 hours; 20 is equal to 2.5 lines ofimprovement for 8 hours; 25 is equal to 3+ lines of improvement for 8.3hours and 35 is equal to 3.75+ lines of improvement for 9 hours.

As demonstrated by comparing the Reading vs. Baseline at 40 cm andEfficacy Indexes of formulas #L33-#L37, formulas containing 1.40% ormore aceclidine are better at correcting presbyopia than those formulascontaining 1.25% aceclidine. Inversely, the lower concentration ofaceclidine results in better overall comfort to the user. The additionof 2.5% mannitol to formulas with 1.45% aceclidine improves overallcomfort but at the expense of reducing the presbyopic correcting effect(compare #L37 with #L47.) This reduction in near vision improvement isexacerbated with the addition of 4.0% mannitol (compare #L47 with #L48.)Increasing aceclidine concentrations to 1.65% or 1.75% overcome thereduction in near vision improvement seen with the addition of mannitol(compare #L47 with #L49 and #L50.)

Further, formulas containing 1.75% aceclidine and 2.5% mannitol have anincreased efficacy and duration in treating presbyopia that iscorrelated with an increase in polysorbate 80 up to 5.0% and theninversely correlated with a decrease in CMC from 1.45% to 1.40% (compareformulas #L66 to #L78.) Optimal formulations are demonstrated by #L77,#L78 and #L85-#L94, which each have the highest improve reading at 40 cmat between 3.5 and 3.75 visual acuity lines and the highest EfficacyIndex scores of 25 to 34, and the longest duration from 7 to 9 hours.The increase in effectiveness and duration of formulas from #L66 to #L78are also inversely correlated with a decrease in tropicamide from0.0275% to 0.01%. This same trend is demonstrated by the increase ineffectiveness (i.e. Reading vs. Baseline 40 cm) when comparing #L85through #L94.

This data demonstrates that mannitol can effectively reduce ciliaryspasms caused by aceclidine, thus reducing the need for a cycloplegicagent such as tropicamide. Further, this data demonstrates that theaddition of a non-ionic surfactant and viscosity agent can furtherenhance the efficacy and duration of compositions containing aceclidine,mannitol and low tropicamide. This data also demonstrates that the useof a cycloplegic agent in aceclidine compositions containing polysorbate80 and CMC is most beneficial to presbyopic correction when thecycloplegic agent is closer to 0.006% than 0.025%. Finally, this datademonstrates that compositions comprising aceclidine and mannitol aresufficient to correct presbyopia with tolerable pain.

Example 12 Use of Further High Tropicamide Formulations

The following examples are of aceclidine formulations containing morethan 0.03% tropicamide.

TABLE 9 High tropicamide formulations #L39 #L40 #L41 #L42 #L43 #L44 #L45#L46 Aceclidine  1.45%  1.45%  1.40%  1.40%  1.40% 1.40% 1.40% 1.40%Tropicamide 0.035% 0.037% 0.040% 0.050% 0.055% 0.06% 0.08% 0.04%Polyoxyl 40  5.5%  5.5%  5.5%  5.5%  5.5%  5.5%  5.5%  5.5% StearateCitrate  0.10%  0.10%  0.10%  0.10%  0.10% 0.10% 0.10% 0.10% Glycerine 0.10%  0.10%  0.10%  0.10%  0.10% 0.10% 0.10% 0.10% CMC  0.75%  0.75% 0.75%  0.75%  0.75% 0.75% 0.75% 0.75% NaCl  0.50%  0.50%  0.50%  0.50% 0.50% 0.50% 0.50% 0.50% Phosphate buffer 3 3 3 3 3 3 3 3 pH 5.0 5.0 5.05.25 5.5 5.25 5.0 5.0 BAK 0.015% 0.015% 0.015% 0.015% 0.015% 0.015% 0.015%  0.015%  Reading vs. 3.5 3.5 3.5 2 1 1 1 3 Baseline 40 cmDuration (hours) 6 6 6 2 2 1 1 6 Ciliary Spasm 1 0.5 0.5 0.5 0.5 0.5 0.50.5 Stinging 1.0 1.0 1.0 0.5 0.25 0.5 1 1 Distance blur none none nonenone none none none none Onset (min) 20-17 20-18 20-19 20-20 20-21 20-2220-23 20-24 Redness 1 hr (0-4) 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Overallcomfort fair good good good good good good good Osmolarity hi hi hi hihi hi hi hi Efficacy index: 21 21 21 4 2 1 1 18 read*dur OVERALL (1-5)** *** *** * ½* ¼* ¼* ***Ciliary spasms scores correspond to the following: 0=no discomfort;0.5=slight sting; 1=noticeable squeeze/discomfort; 2=pain for less than30 minutes; 3=pain for 1 hour or more; and 4=severe to intolerable pain.

As demonstrated by formulas #L39-#L41 and compared to formulas #L74-#L78in Table 8, formulas containing about 1.40% to about 1.45% aceclidine,about 0.035% to about 0.04% tropicamide, about 5.5% polyoxyl 40 stearateand about 0.75% CMC are almost, but not quite as effective at treatingpresbyopia as formulas containing about 1.65% to about 1.75% aceclidine,about 2.5% mannitol, about 5% polysorbate 80, about 1.40% CMC formulas.This effectiveness decreases dramatically when tropicamide is increasedto about 0.05% to about 0.08% tropicamide.

Example 13. Use of a compound containing mannitol Formulation:

-   aceclidine 1.75% w/v-   tropicamide 0.006% w/v-   mannitol 2.5% w/v-   polysorbate 80 2.75% w/v-   NaCl 0.5% w/v-   hydroxypropylmethyl cellulose 0.5% -1.80% w/v-   phosphate buffer 3 mM-   pH 5.0, and-   BAK 0.020% as preservative.

Method:

The subject instilled 2 drops of the above formulation in each eye andthe excess wiped from lids and lashes.

Results:

Within 20 minutes, near vision improvement of about 3 lines of visualacuity was noted with very slight dimming. Throughout the day nearvision remained enhanced with no loss of distance vision. Further, ifthe subject previously suffered from any mild refractive errors distancevision was improved. Over a 5-8 hour period the pupil begins to slightlyrecover, and after a few hours the minimal dimming was no longer noted.Both excellent near vision near onset, and possibly still slightlyimproved near vision continued as the pupil slightly begins to increasefrom its minimal size earlier in the day.

Example 14. Use of a Preferred Embodiment Optimizing Tropicamide andHydroxypropyl Methyl Cellulose

Composition

Aceclidine 1.75% w/v Tropicamide 0.010% w/v  Mannitol 2.50% w/vPolysorbate 80 3.50% w/v NaCl 0.50% w/v HPMC 1.25% w/v BAK 0.02% w/vPhosphate buffer 3 mM pH 5.00

Method

The subject instilled 2 drops of the above formulation in each eye as 1single drop each eye and a second drop after 5 minutes.

Results:

Comfort, duration and efficacy were assessed. Stinging upon instillationand over the first hour was minimal with a score of 0.25 out of 4.Redness over the first hour was also minimal with a score of 0.5 out of4 assessed at 20 minutes. Onset of vision improvement occurred with thefirst 20 to 25 minutes after instillation. Baseline near vision (i.e. 40centimeters) was improved by 3.5 lines of visual acuity. Improvement innear vision lasted for 8.5 hours. Comparing this formula to those inTable 8, the Efficacy Index score was 29.75. Substituting HPMC 1.80% w/vwith HPMC 1.65% w/v resulted in a slight reduction in near visionimprovement to 3.25 lines of visual acuity and a slight reduction induration to just over about 6 hour. Comparing this formula to those inTable 8, the Efficacy Index score was 19.5.

Example 15. Use of a Compound Containing Mannitol with Various NonionicSurfactants Compositions

Table 10 lists the active ingredients, excipients and theirconcentrations for compositions with both tested and prophetic examplesof nonionic surfactants.

Methods

The subject independently instilled 2 drops of the above compositions ineach eye and the excess wiped from lids and lashes.

Results

All nonionic surfactants tested demonstrate substantial near visionimprovement. Of those tested only Brij® 35 was marginal due to thesignificant corneal irritation, hyperemia and reduced duration thatresulted. Polysorbate 80 and poly 35 castor oil were most preferred,polyoxyl 40 stearate and poloxamer 407 excellent as well. However,polyoxyl 40 stearate caused a precipitate reaction with celluloseviscosity agents and added other stability issues.

Comfort and duration for each non-ionic surfactant were also tested andare noted in Table 10. Stinging and Redness are based on a scale of 0 to4 with 0 being none and 4 being the most severe. Other than Brij® 35stinging and redness were mild to nearly absent. Duration was excellentfor each nonionic surfactant tested.

TABLE 10 Comparing efficacy and comfort of various nonionic surfactantsPolyoxyl Polyoxyl Poloxamer Tyloxapol Polysorbate 20 Poloxamer 188Solulan C-24 % w/v Polysorbate 80 35 castor oil 40 stearate 407 Brij ®35 (prophetic) (prophetic) (prophetic) (prophetic) Aceclidine 1.75%1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide 0.006% 0.006%  0.005%  0.005%  0.005%  0.006%  0.006%  0.006%  0.006%  Mannitol 2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5% Nonionicsurfactant  3.5%  3.5%  3.5%  3.5%  3.5%  3.5%  3.5%  3.5%  3.5% NaCl0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% HPMC 1.80% 1.80%1.80% 1.80% 1.80% 1.80% 1.80% 1.80% 1.80% BAK 0.02% 0.02% 0.02% 0.02%0.02% 0.02% 0.02% 0.02% 0.02% Phosphate buffer 3 mM 3 mM 3 mM 3 mM 3 mM3 mM 3 mM 3 mM 3 mM pH 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00Stinging 0.25 0 0.5 0.5 2 0-2 0-2 0-2 0-2 Redness 1 hr 0.5 0.25 0.75 12.5 0.25-2.5  0.25-2.5  0.25-2.5  0.25-2.5  Reading vs. 3.75 3.5 3 3 2  2-3.5   2-3.5   2-3.5   2-3.5 Baseline (40 cm) Duration (hours) 10 9 77 4 4-8 4-8 4-8 4-8 Efficacy Index 37.5 31.5 21 21 8   8-37.5   8-37.5  8-37.5   8-37.5 read*dur Onset (min) 20-25 20-25 20-25 20-25 30-4020-40 20-40 20-40 20-40

Example 16. Use of a Compound Containing Optimizing Nonionic Surfactantand Antioxidant Additives and Concentrations Compositions

Aceclidine 1.75% w/v Tropicamide 0.010% w/v  Mannitol 2.50% w/vPolysorbate 80 4.00% w/v NaCl 0.00% w/v HPMC 1.25% w/v (high MW equalingviscosity of about 400 cps units) BAK 0.02% w/v Sorbate 0.12% w/v BAK0.02% w/v EDTA 0.01% Citrate buffer 3 mM pH 5.00

Method

2 subjects instilled 2 drops each of the above formulation in each eyeabout 5 minutes apart.

Results:

-   Comfort, duration and efficacy were assessed. Stinging upon    instillation and over the first hour was minimal for each subject    with a score of 0.50 out of 4 for about 15 seconds. Redness over the    first hour was also minimal for each subject with a score of 0.25    out of 4 assessed at 20 minutes. Onset of vision improvement    occurred with the first 20 to 25 minutes after instillation. For    subject 1 baseline near vision (i.e. 40 centimeters) was improved by    4.0-4.25 lines of visual acuity and lasted for 11.5 hours. For    subject 2 baseline near vision was improved by 3.5 lines of visual    acuity and lasted for 9.5 hours. The Efficacy Index score was 47.38    and 33.25, among the highest achieved for any formulation.

Example 17. Aceclidine Compositions for Cold Chain Storage (Prophetic)

TABLE 11 Cold Chain Storage Compositions Composition CS#1 CS#2 CS#3 CS#4CS#5 CS#6 CS#7 CS#8 Aceclidine 1.75% 1.75% 2.50% 4.00% 2.00% 1.65% 1.75%1.75% Mannitol 2.50% 2.50% 2.50% 2.50% 2.50% — 2.50% 2.50% Polysorbate80 4.00% 4.00% 4.00% 4.00% 4.00% — 4.00% 4.00% HPMC 1.25% 1.25% 1.25%1.25% 1.25% 0.75% 1.10% 1.10% Sodium Citrate 0.10% 0.10% 0.10% 0.10%0.10% — 0.10% 0.10% BAK 0.02% 0.02% 0.02% 0.02% — — 0.02% 0.02% SorbicAcid 0.12% 0.12% 0.10% 0.12% 0.12% 0.12% 0.12% 0.12% Disodium 0.10%0.10% 0.10% 0.10% — — 0.10% 0.10% Edetate Dihydrate Sodium — — 0.10% — —— — — Ascorbate Sodium — — — 0.10% — — — — bisulfate Sodium — — — —0.10% — — — metabisulfite pH 5.0 6.0 6.0 6.5 6.5 7.0 5.0 6.0 N2fill/purge Yes Yes Yes Yes Yes No No No Composition CS#9 CS#10 CS#11CS#12 CS#13 CS#14 CS#15 CS#16 Aceclidine 4.00% 0.50% 2.50% 3.00% 4.00%4.00% 4.00% 4.00% Mannitol — — — — — — — — Polysorbate 80 — — — — — — —— HPMC — — — 0.75% 1.25% 1.25% 1.25% 1.25% Sodium Citrate — — — — —0.10% — — BAK — — — — — — — — Sorbic Acid — — — — — — — — Disodium — — —— — — — — Edetate Dihydrate Sodium — — — — — — — — Ascorbate Sodium — —— — — — 0.10% — bisulfate Sodium — — — — — — — 0.10% metabisulfite pH5.0 7.0 6.0 6.0 6.0 6.0 6.0 6.0 N2 fill/purge No No Yes Yes Yes Yes YesYes Composition CS#17 CS#18 CS#19 CS#20 Aceclidine 4.00% 4.00% 4.00%4.00% Mannitol 2.50% 2.50% 2.50% 2.50% Polysorbate 80 4.00% 4.00% 4.00%4.00% HPMC 1.25% 1.25% 1.25% 1.25% Sodium Citrate 0.10% — — 0.25% BAK0.02% 0.02% 0.02% 0.02% Sorbic Acid 0.12% 0.12% 0.12% 0.12% Disodium — —— — Edetate Dihydrate Sodium — — — — Ascorbate Sodium — 0.10% — —bisulfate Sodium — — 0.10% — metabisulfite pH 6.0 6.0 6.0 6.0 N2fill/purge Yes Yes Yes Yes

Methods

Aceclidine cold chain storage compositions CS#1-5 and 11-20 were filledinto vials each under a nitrogen overlay followed by a nitrogen purge ofremaining headspace. CS#6-10 were filled into vials each under ambientair and headspace. 1 vial of each composition was stored at 25 degreesCelsius and the other was stored at 5 degrees Celsius.

Results

TABLE 12 Aceclidine Cold Chain Storage Composition Stability CompositionCS#9 CS#10 CS#11 CS#12 CS#13 CS#14 25 Celsius 4 5 — — — — 90% Stability(weeks) 5 Celsius 7 8 12 12.5 15 18 90% Stability (months) CompositionCS#15 CS#16 CS#17 CS#18 CS#19 CS#20 25 Celsius — — — — — — 90% Stability(weeks) 5 Celsius 18 18 20 20 20 22 90% Stability (months)

As seen in FIG. 4, CS#3-5 contaiing 0.10% sodium ascorbate, 0.10% sodiumbisulfate or 0.10% sodium metabisulifite were stable for about 2 monthsat 25 degrees Celsius and for about 26 months at 5 degrees Celsius.

As seen in Table 12, filling vials under a nitrogen overlay and nitrogenpurge of the head space resulted in a cold storage stability increase of4-5 months. The addition of HPMC further increased stability another 3months; sodium citrate, sodium bisulate or sodium metabisulifite another3 months; and the further addition of sorbic acid and BAK another 2months further increased the length of stability. CS#20 increasedstability up to 22 months.

Example 18. Stability in Mylar® Lined Pouches

Aceclidine formulations of the present invention were placed incontainers that were subsequently placed in biaxially-orientedpolyethylene terephthalate lined pouches at −20, 5 and 25 C for up to 3months. Aceclidine total related substances was recorded at 1, 2, 3 and6 months. Results of this study can be seen in Table 13, below.

Mylar® was used as the source of biaxially-oriented polyethyleneterephthalate. Mylar is a registered trademark of and available fromDuPont Teijin Films US Limited.

TABLE 13 Aceclidine Total Related Substances after Storage ConditionsInitial Result One Month Result Two Month Result Three Month Result SixMonth Result Total % Change Unpouched (5 C.) 0.41% 0.55% 0.51% 0.05%0.49%   0.08% Unpouched (25 C.) 0.58% 1.45% 1.39% 4.87%   4.46% Pouched(5 C.) 0.54% 0.35% 0.47%   0.06% Pouched (25 C.) 0.55% 1.26% 0.36%−0.05% Pouched (−20 C.) 0.74% 0.25% 0.00% −0.41% Pouched (5 C.) 0.50%0.18% 0.00% −0.41% Pouched (25 C.) 0.74% 0.31% 0.00% −0.41%

As seen in Table 13, the use of a Mylar® lined pouches helped maintainaceclidine potency by reducing degradation rate. Specifically, compareUnpouched at room temperature (25 C) total % change of 4.46% to the-0.05% and 0.041% total % change of Pouched at room temperature (25 C).

Example 19. Aceclidine Potency Following Storage

Aceclidine formulations of the present invention were placed incontainers that were subsequently placed in biaxially-orientedpolyethylene terephthalate lined pouches at −20, 5 and 25 C for up to 3months. Aceclidine potency was recorded at 1, 2, 3 and 6 months. Resultsof this study can be seen in Table 14, below.

TABLE 14 Aceclidine Potency after Storage Percent change Between Initialand Sample Initial Result One Month Result Two Month Result Three MonthResult Six Month Result Six Month Results Unpouched (5 C.) 99.70% 99.3%102.0% 100.0% 100.5%    0.8% Unpouched (25 C.) 98.2% 101.9%  98.2% 97.7%−2.0% Pouched (5 C.) 100.0%   99.7% 100.8%    1.1% Pouched (25 C.) 98.4% 97.5% 94.9% −4.8% Pouched (−25 C.) 99.60% 98.5% 101.4% 103.1%    3.5%Pouched (5 C.) 99.5% 102.3% 102.2%    2.6% Pouched (25 C.) 103.0%  99.0% 96.0%   3.6%

As seen in Table 14, the use of 5 degrees Celsius storage helpedmaintain aceclidine potency. Specifically, compare Unpouched at roomtemperature (25 C) total % change of −2.0% potency to the 0.8% change ofUnpouched in cold storage (5 C) for the initial result of 99.70% andcompare Unpouched at room temperature (25 C) total % change of 3.6%potency to the 2.6% change of Unpouched in cold storage (5 C) for theinitial result of 99.60%.

What is claimed is:
 1. A method of stabilizing an ophthalmic drugcomprising the following steps: a) adding a surfactant and a viscosityenhancer to the ophthalmic drug to create a composition wherein thecomposition has a viscosity of about 25 centipoise or less at a shearrate of 1/1000 per second at 25 degrees Celsius and a viscosity of about70 centipoise or more at shear rate of 1 per second at 25 degreesCelsius; b) filling the composition from step a) into a container; andc) storing the container at a temperature from about 2 degrees Celsiusto about 25 degrees Celsius.
 2. The method of claim 1, wherein theophthalmic drug is selected from the group consisting of aceclidine,latanoprost and combinations thereof.
 3. The method of claim 1, whereinthe ophthalmic drug is aceclidine.
 4. The method of claim 1, wherein thesurfactant is selected from the group consisting of polysorbates,poloxamers, polyoxyl alkyls, cyclodextrins, ammonium lauryl sulfate,dioctyl sodium sulfosuccinate, sodium laureth sulfate, linearalkylbenzene sulfonate, sodium dodecyl sulfate,perfluorooctanesulfonate, sodium lauryl sarcosinate, sodium myrethsulfate, sodium pareth sulfate, sodium stearate, lignosulfonate, sodiumlauryl sulfate, a olefin sulfonate, ammonium laureth sulfate, sodiumester lauryl sulfate, benzalkonium chloride, benzethonium chloride,methylbenzethonium chloride, cetylpyridinium chloride, alkyl-dimethyldichlorobenzene ammonium chloride, dequalinium chloride, phenamyliniumchloride, cetyl trimethylammonium bromide, cetyl trimethylammoniumchloride, cetrimonium bromide, cethexonium bromide, alkyl-amphoacetates,alkenyl-amphoacetates, alkyl-amphodiacetates, alkenyl-amphodiacetates,alkylamphopropionates, alkylamphodipropionates, alkyl amphohydroxypropylsultaines and combinations thereof.
 5. The method of claim 1, whereinthe viscosity enhancer is selected from the group consisting of gums,cellulose derivatives, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, gellan, carrageenan, alginic acid, carboxyvinyl polymer andcombinations thereof.
 6. The method of claim 1, wherein the viscosity atshear rate of 1 per second at 25 degrees Celsius is about 150 centipoiseor more.
 7. The method of claim 6, wherein the viscosity at shear rateof 1 per second at 25 degrees Celsius is about 300 centipoise or more.8. The method of claim 1, wherein the container is stored at atemperature from about 2 to about 8 degrees Celsius.
 9. The method ofclaim 8, wherein the container is stored at a temperature of about 5degrees Celsius.
 10. The method of claim 1, wherein the composition isfilled into the container under an inert gas overlay.
 11. The method ofclaim 1, wherein the filling step creates a head space in the containerand the head space is purged with an inert gas.
 12. The method of claim1, wherein the container comprises a closure and a vessel wherein aportion of the closure and a portion of the vessel are sealed with ananti-leaching material selected from the group consisting ofbiaxially-oriented polyethylene terephthalate, polytetrafluorethyleneand aluminum foil.
 13. The method of claim 1, wherein the container isdisposed in a second container that is formed with or lined with ananti-leaching material selected from the group consisting ofbiaxially-oriented polyethylene terephthalate, polytetrafluorethyleneand aluminum foil.
 14. A container comprising an ophthalmic drugprepared by the process comprising the steps of: a) providing acontainer; b) filling the container with a composition comprising anophthalmic drug, a surfactant and a viscosity enhancer, preferably underan inert gas overlay, preferably nitrogen, wherein the composition has aviscosity of about 25 centipoise or less at a shear rate of 1/1000 persecond at 25 degrees Celsius and a viscosity of about 70 centipoise ormore at shear rate of 1 per second at 25 degrees Celsius; c) capping thecontainer; and d) storing the container at a temperature from about 2 toabout 25 degrees Celsius.
 15. The container of claim 14, wherein theophthalmic drug is selected from the group consisting of aceclidine,latanoprost and combinations thereof.
 16. The container of claim 14,wherein the ophthalmic drug is aceclidine.
 17. The container of claim14, wherein the surfactant is selected from the group consisting ofpolysorbates, poloxamers, polyoxyl alkyls, cyclodextrins, ammoniumlauryl sulfate, dioctyl sodium sulfosuccinate, sodium laureth sulfate,linear alkylbenzene sulfonate, sodium dodecyl sulfate,perfluorooctanesulfonate, sodium lauryl sarcosinate, sodium myrethsulfate, sodium pareth sulfate, sodium stearate, lignosulfonate, sodiumlauryl sulfate, a olefin sulfonate, ammonium laureth sulfate, sodiumester lauryl sulfate, benzalkonium chloride, benzethonium chloride,methylbenzethonium chloride, cetylpyridinium chloride, alkyl-dimethyldichlorobenzene ammonium chloride, dequalinium chloride, phenamyliniumchloride, cetyl trimethylammonium bromide, cetyl trimethylammoniumchloride, cetrimonium bromide, cethexonium bromide, alkyl-amphoacetates,alkenyl-amphoacetates, alkyl-amphodiacetates, alkenyl-amphodiacetates,alkylamphopropionates, alkylamphodipropionates, alkyl amphohydroxypropylsultaines and combinations thereof.
 18. The container of claim 14,wherein the viscosity enhancer is selected from the group consisting ofgums, cellulose derivatives, polyethylene glycol, polyvinyl alcohol,polyvinyl pyrrolidone, gellan, carrageenan, alginic acid, carboxyvinylpolymer and combinations thereof.
 19. The container of claim 14, whereinthe viscosity at shear rate of 1 per second at 25 degrees Celsius is ofabout 150 centipoise or more.
 20. The container of claim 19, wherein theviscosity at shear rate of 1 per second at 25 degrees Celsius is ofabout 300 centipoise or more.
 21. The container of claim 14, wherein thecontainer is stored at a temperature from about 2 to about 8 degreesCelsius.
 22. The container of claim 21, wherein the container is storedat a temperature of about 5 degrees Celsius.
 23. The container of claim14, wherein after step b) and prior to step c) a head space createdduring the filling step is purged with an inert gas.
 24. The containerof claim 14, wherein the inert gas is nitrogen.